Francesco Punzo

Interfacial Free Energy Driven Nanophase Separation in Poly(3-hexylthiophene)/[6,6]-Phenyl-C61-butyric Acid Methyl Ester Thin Films

The nanostructure of thermally annealed thin films of poly(3-hexylthiophene) (P3HT) and [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) blends on hydrophobic and hydrophilic substrates was studied to unravel the relationship between the substrate properties and the phase structure of polymer blends in confined geometry. Indeed, the nature of the employed substrates was found to affect the extent of phase separation, the PCBM aggregation state and the texture of the whole system. In particular, annealing below the melting temperature of the polymer yielded the formation of PCBM nanometric crystallites on the hydrophobic substrates, while mostly amorphous microscopic aggregates were formed on the hydrophilic ones. Moreover, while an enhanced in-plane orientation of P3HT lamellae was promoted on hydrophobic substrates, a markedly tilted geometry was produced on the hydrophilic ones. The observed effects were interpreted in terms of a simple model connecting the interface free energy for the blend films to the different polymer chain mobility and diffusion velocity of PCBM molecules on the different substrates.

Crystal Morphologies and Polymorphs in Tolbutamide Microcrystalline Powder

The growing interest of pharmaceutical companies toward the crystal morphology prediction of active pharmaceutical ingredients is a consequence of the dramatic effect of the crystal habit on the tableting behavior of drugs. In order to help the optimization of the industrial process, molecular mechanics calculations together with X-ray diffraction analysis and optical microscopy (OM) were used to shed light over the structural properties of N-(butylcarbamoyl)-4-methylbenzenesulfonamide-commercially known as tolbutamide-a drug used in the management of type II diabetes, especially in elderly diabetics because of its rapid metabolism. As there are several known polymorphs of this molecule, we first defined, by means of a quantitative phase analysis, performed by X-ray powder diffraction, which and how much each of the five crystallographic structures present in the Cambridge Crystallographic Database represent the commercial crystalline powder. The structures of the resulting candidates were first analyzed by means of molecular mechanics, and the crystal morphologies of the compounds were therefore predicted and compared with the ones observed by means of OM. Analogies and differences among the different morphologies, together with the potential role of crystallization solvents, were commented in the attempt to bridge the gap between the molecular structure-that is, the atomic point of view-and the crystal habit.

Experimental and in silico characterization of a biologically active inosose

Inositols have been recently reported to show a biological activity as inhibitors of both glycosidase and amyloid-β protein. After having harvested good crystals suitable for single crystal X-ray diffraction, we performed a comparison with the data inferred by means of a molecular dynamics simulation, based on the use of an appropriate Force Field coupled to the most performing charging scheme. This approach allowed a detailed analysis extended to ultra-fine details, such as atomic displacement parameters. It confirmed the good validity of a robust approach already tested by us in previous studies. A NMR analysis of the molecule in solution was also carried out, to compare the structural findings suggested by the X-ray analysis with the ones in solution and avoid confining them to the solid-state. In this framework, we investigated the above-mentioned inhibiting activity of a class of inososes, by means of a molecular docking investigation, which proved the suggested validity of the studied compound as inhibitor of the α-glucosidase.

Potassium caffeate/caffeic acid co-crystal: the rat race between the catecholic and carboxylic moieties in an atypical co-crystal†

The vast literature concerning caffeic acid and its derivatives lacks any reference to the solid state structures of its inorganic salts as these crystals are quite difficult grow. Most of the already published works deal with computational studies of these compounds as well as investigations of their behaviour in solution. Having obtained good quality potassium caffeate/caffeic acid co-crystals, we solved their structure and used a robust approach, already applied to caffeic acid alone, to compare the X-ray structure with the one inferred by Molecular Dynamics (MD), focusing our attention on the structure-property relationships. The reliability of this method is confirmed by the overall agreement extended up to the anisotropic displacement parameters calculated, on one hand, by means of MD and the ones gathered, on the other hand, by X-ray measurements. Moreover, the lack of experimental evidence of an enthalpically favored polymorph, arising from the MD calculations, were explained on the basis of the Shannons entropy.

Structural characterization of LASSBio-1289: a new vasoactive N-methyl-N-acylhydrazone derivative

LASSBio-1289 compound has been found to promote intense vasodilation and antihypertensive activity. It is an innovative compound, without structural similarities to the three main classes of calcium antagonists (1,4-dihydropyridines, benzothiazepines and phenylalkylamines) commonly used. A complete knowledge of the structure, including stereochemistry, is essential to lead optimization in drug discovery. For this reason, in this work we determined the crystal structure of this novel vasoactive N-methyl-N-acylhydrazone derivative by means of X-ray powder diffraction data and an ab initio simulating annealing approach, allowing us to observe the relative configuration E of the imine double bond and its conformation as well as its most relevant intermolecular interactions. These findings were also checked by a FTIR analysis and confirmed in solution by NMR. The compound crystallized under a monoclinic crystal system with space group P21/c and unit cell parameters a = 14.5118(3) A, b = 12.1374(2) A, c = 7.5498(1) A, β = 91.113(1)°, V = 1329.53(4) A3, Z = 4, Z′ = 1 and ρcalc = 1.44042(4) g cm−3. Moreover, a crystal morphology prediction, experimentally compared with SEM inferred images, allowed a direct comparison of the microcrystalline habit and quality, allowing a study of the potential solvent effect on the crystal growth.

A top-down approach to crystal engineering of a racemic Δ2-isoxazoline.

The crystal structure of racemic dimethyl (4RS,5RS)-3-(4-nitrophenyl)-4,5-dihydroisoxazole-4,5-dicarboxylate, C13H12N2O7, has been determined by single-crystal X-ray diffraction. By analysing the degree of growth of the morphologically important crystal faces, a ranking of the most relevant non-covalent interactions determining the crystal structure can be inferred. The morphological information is considered with an approach opposite to the conventional one: instead of searching inside the structure for the potential key interactions and using them to calculate the crystal habit, the observed crystal morphology is used to define the preferential lines of growth of the crystal, and then this information is interpreted by means of density functional theory (DFT) calculations. Comparison with the X-ray structure confirms the validity of the strategy, thus suggesting this top-down approach to be a useful tool for crystal engineering.

Structural feature evolution – from fluids to the solid phase – and crystal morphology study of LASSBio 1601: a cyclohexyl-N-acylhydrazone derivative

LASSBio-1601, a cyclohexyl-N-acylhydrazone derivative, was synthesized as part of a research program to develop a series of anti-inflammatory and analgesic compounds. A complete knowledge of the structure, including stereochemistry, is essential to lead optimization in drug discovery. In this work different techniques were used to obtain detailed information on the evolution of the structural characteristics of this compound from fluids to the solid state, in order to shed some light on the conformation of the molecule in different physical states. By quoting the aforementioned structural analysis, a crystal morphology prediction, compared with the experimentally inferred SEM images, has been performed to analyze potentially alternative routes useful for pharmaceutical tableting.

Polymeric membranes conditioning for sensors applications: mechanism and influence on analytes detection

In this work, we studied an ion-exchange membrane based on an inert polymer skeleton in which it is dispersed and anchored a molecule with charged groups able to discriminate and bind positive or negatively charged ions present in a sample. In order to be ready to work, electromembranes need a complex procedure called activation or conditioning. Although most of the known literature looks at the subject from an electrochemical point of view, we put forward a structural approach. Membrane conditioning, in fact, is considered a required step to improve sensor performances and to allow the collection of reproducible data. Even if this operation is carefully followed by all the operators working with sensors equipped with a membrane, it looks like that a thoroughly explanation of the working mechanism and a detailed balance of cost and gains has still not been carried out. As a consequence, we suggest a bulk or membrane approach, where the landscape is mainly characterized by the long-range structure of the membrane itself. Our findings suggest that membrane conditioning has to be carried out carefully and the advantages of this pre-treatment can be appreciated especially for very low concentration measurements. The need for the conditioning mainly results from the necessity of a complete permeation of all the different tortuous channels constituting the membrane itself.

Functional hybrid co-crystals of humic substances: a growth forecast

Basing our reasoning on the only known and available crystalline structure of a hybrid co-crystal of caffeic acid, we extended our study to the analysis of the behaviour of another humic substance, the protocatechuic acid. The abilities and tendencies of both these compounds to give rise to stable hybrid co-crystals with the elements of group I were studied by predicting, via molecular dynamics simulations, their crystalline setups on the basis of a detailed energetic analysis, which allows the detection of the most stable possible structures and their layouts. Without claiming to have performed an ab initio crystal structure prediction, we tried instead to determine the tendencies of a specific set of humic substances to give rise to a particular type of hybrid co-crystals.

(+)-Methyl (1R,2S)-2-{[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]methyl}-1-phenylcyclopropanecarboxylate [(+)-MR200] Derivatives as Potent and Selective Sigma Receptor Ligands: Stereochemistry and Pharmacological Properties

Methoxycarbonyl-1-phenyl-2-cyclopropylmethyl based derivatives cis-(+)-1a [cis-(+)-MR200], cis-(-)-1a [cis-(-)-MR201], and trans-(±)-1a [trans-(±)-MR204], have been identified as new potent sigma (σ) receptor ligands. In the present paper, novel enantiomerically pure analogues were synthesized and optimized for their σ receptor affinity and selectivity. Docking studies rationalized the results obtained in the radioligand binding assay. Absolute stereochemistry was unequivocally established by X-ray analysis of precursor trans-(+)-5a as camphorsulfonyl derivative 9. The most promising compound, trans-(+)-1d, showed remarkable selectivity over a panel of more than 15 receptors as well as good chemical and enzymatic stability in human plasma. An in vivo evaluation evidenced that trans-(+)-1d, in contrast to trans-(-)-1d, cis-(+)-1d, or cis-(-)-1d, which behave as σ1 antagonists, exhibited a σ1 agonist profile. These data clearly demonstrated that compound trans-(+)-1d, due to its σ1 agonist activity and favorable receptor selectivity and stability, provided an useful tool for the study of σ1 receptors.