Ernest Meštrović

One‐Pot Mechanosynthesis with Three Levels of Molecular Self‐Assembly: Coordination Bonds, Hydrogen Bonds and Host–Guest Inclusion

Liquid-assisted grinding (LAG) was used to combine three levels of molecular self-assembly into a one-pot mechanochemical approach for the construction of metal-organic materials. The approach was applied for the construction of three adducts of cobalt(II) dibenzoylmethanate with isonicotinamide, nicotinamide and imidazole, to screen for their inclusion compounds. The one-pot process consists of: i) The coordination-driven binding of addends to the equatorially-protected metal ion, resulting in wheel-and-axle-shaped complexes; ii) self-assembly of resulting complexes by way of hydrogen-bonded synthons to form metal-organic inclusion hosts; iii) in situ inclusion of the grinding liquid in the resulting host. This approach provided quantitatively and within 20 min the known inclusion compounds of the bis(isonicotinamide) adduct in a single synthetic step. Changing the liquid phase in LAG was used to explore the inclusion behaviour of new wheel-and-axle adducts with nicotinamide and imidazole, revealing several inclusion compounds, as well as two polymorphs, of the bis(nicotinamide) host. Preliminary results suggest that one-pot LAG is superior to solution synthesis in screening for metal-organic inclusion compounds. The difference between the methods is rationalised in terms of reactant solubility and solvent competition. In contrast to the nicotinamide adduct, the bis(imidazole) adduct did not form inclusion compounds. The difference in the inclusion properties of the two adducts is rationalised by structural information gathered by single crystal and powder X-ray diffraction.

A sildenafil cocrystal based on acetylsalicylic acid exhibits an enhanced intrinsic dissolution rate

Cocrystallisation of sildenafil with acetylsalicylic acid yields a 1u2006:u20061 sildenafil–acetylsalicylic-acid cocrystal, as well as a 1u2006:u20061u2006:u20061 cocrystal salt involving a sildenafil cation, acetylsalicylate and salicylic acid. The 1u2006:u20061 acetylsalicylic-acid-based cocrystal exhibits an enhanced intrinsic dissolution rate, as compared to sildenafil citrate (the active ingredient of Viagra®).

VO⋯C interactions in crystal structures of oxovanadium-coordination compounds

A survey of the Cambridge Structural Database (CSD) revealed the existence of a new supramolecular homosynthon in oxovanadium coordination compounds (OCCs) that is based on non-covalent VO⋯C interactions. VO⋯C close contacts were found in 38.7% of structures containing vanadyl or pervanadyl groups. The VO⋯C interaction is clearly distinguishable from a putative VO⋯H–C hydrogen bond upon analysis of OCC crystal structures deposited in the CSD. In the majority of structures, the OCCs assemble to form dimers or polymers. The VO⋯C interactions were also found to lead to self-assembly of two new oxovanadium β-diketonate complexes into dimers in the solid state.

Forced degradation of nepafenac: Development and validation of stability indicating UHPLC method

This paper presents stability study of the nonsteroidal anti-inflammatory drug (NSAID) nepafenac. In order to investigate stability of nepafenac, it was subjected to forced degradation under different stress conditions: acid and base hydrolysis, oxidation, humidity, heat and light. A novel stability indicating reverse phase ultra high performance liquid chromatographic (UHPLC) method coupled to ultraviolet detector has been developed to separate nepafenac and all related compounds (2-aminobenzophenone, Cl-thionepafenac, thionepafenac, Cl-nepafenac, hydroxy-nepafenac, and cyclic-nepafenac). Efficient chromatographic separation was achieved on a Waters Acquity BEH C18 stationary phase with a gradient elution. Quantification was carried out at 235 nm at a flow rate of 0.6 mL/min(-1). The resolution between nepafenac and six potential impurities is found to be greater than 2.0. The developed method was validated with respect to specificity, LOD, LOQ, linearity, precision, accuracy and robustness. The r(2) values for nepafenac and six potential impurities were all greater than 0.999. The developed method is capable to detect impurities of nepafenac at a level of 0.005% with respect to test concentration of 1.0mg/mL. Significant degradation is observed in acid, base and oxidative degradation conditions and degradation products (DPs) were identified using mass spectrometry analysis; two of them were found to be a known process related impurities (hydroxy- and cyclic-nepafenac) whereas four degradation products were identified as new degradation impurities. The forced degradation samples were assayed against a qualified reference standard and the mass balance was found to be close to 99.5%.

(1,10-Phenanthroline-κ2N,N′)bis­(2,2,6,6-tetra­methyl­heptane-3,5-dionato-κ2O,O′)nickel(II)

The title compound, [Ni(C11H19O2)2(C12H8N2)], was obtained from the reaction of bis(2,2,6,6-tetramethylheptane-3,5-dionato)nickel(II), [Ni(dpm)], and 1,10-phenanthroline (phen). The NiII ion is coordinated by four O atoms from two dpm ligands and two N atoms from a phen ligand in a slightly distorted octahedral environment. The methyl C atoms of two of the tert-butyl groups are disordered over two sites, having approximate occupancies of 0.85 and 0.15 for the two components. In the crystal structure, there are no direction-specific interactions. Thermal studies showed that the title complex is stable to 623u2005K.

Production of stable amorphous form by means of spray drying

ABSTRACT Spray drying is a very useful method for manufacturing of amorphous solid materials. This is mainly due to the possibility of fast solvent evaporation that leads to a rapid transformation of solution to a solid state. Besides evaporation kinetics, there are various process parameters that influence physical and chemical characteristics of such obtained material. The possibility of obtaining a stable amorphous structure of the active pharmaceutical ingredient in a spray dryer was examined. A solution of the hydrochloride crystalline structure of the active pharmaceutical ingredient in a mixture of water and acetonitrile was dried at different temperatures and flowrates of nitrogen used for atomization, as well as the flowrates of the solution. The influence of the process conditions on the properties of the product was analyzed. The final dried products were characterized and identified with a variety of analytical and physical methods. The results showed that a stable amorphous structure of the high purity active pharmaceutical ingredient is obtained, and that the optimal conditions of the process are defined. The amorphous structure is stable at temperatures below 200°C when it is transformed into a new crystal structure. Conditions of high relative air humidity lead to partial transformation.