João Canotilho

An insight into solvent-free diimide porphyrin reduction: a versatile approach for meso-aryl hydroporphyrin synthesis

This paper describes an environmentally sustainable synthetic method for the preparation of a set of meso-aryl hydroporphyrins, namely chlorins and bacteriochlorins, via reduction of porphyrins with diimide, in the total absence of solvents and bases. Thermomicroscopy studies clearly showed that the process is a typical solvent-free reaction.

A thermodynamic based approach on the investigation of a diflunisal pharmaceutical co-crystal with improved intrinsic dissolution rate

A thermodynamic based approach is used to investigate diflunisal+nicotinamide binary and solution mixtures. A 2:1 co-crystal could be prepared by liquid assisted ball mill grinding and by solution crystallization from ethanol. The diflunisal+nicotinamide+ethanol ternary phase diagram points out conditions for co-crystal scaling-up. From the diflunisal+nicotinamide binary phase diagram, besides identification of the co-crystal stoichiometry, two additional useful binary compositions, eutectic mixtures, were characterized. From a solution enthalpy based approach, the enthalpic stabilization of the co-crystal relative to the pure solid components is quantified. Intrinsic dissolution rate, IDR, in test conditions consistent with USP requirements, including those referred in the diflunisal tablet monograph, were carried out, indicating that the co-crystal improves diflunisal IDR by about 20%. The systematic study of diflunisal+nicotinamide mixtures presented in this work is of particular interest due to the relevance of diflunisal, both as a non-steroidal anti-inflammatory drug and also due to the potentiality of orally administrated diflunisal in familial amyloid polyneuropathy.

Study of Polymorphism From DSC Melting Curves; Polymorphs of Terfenadine

Terfenadine samples prepared by crystallization in different media and supersaturation conditions were used to investigate the polymorphism of the substance. The study was based on DSC melting curves. An empirical parametric equation was used for modelling the experimental data. The signal recorded was resolved into the corresponding overlapping peak components by fitting analysis. Four polymorphic phases were identified.

A study of the structure of the pindolol based on infrared spectroscopy and natural bond orbital theory.

Beta-adrenoceptor-blocking agents (beta-blockers) are on the list of the top selling drugs. Pindolol is a representative of this type of compound, either from the structural point of view, or as reference for comparison of the pharmacokinetic properties of the beta-blockers. A study of the pindolol structure based on infrared spectroscopy and natural bond orbital (NBO) theory is the main aim of the present research. FTIR spectra of the solid pindolol were recorded from 4000 to 400cm(-1), at temperatures between 25 and -170 degrees C. For spectral interpretation, the theoretical vibrational spectra of the conformer present in the solid was obtained at the B3LYP/6-31G* level of theory. NBO analysis of the reference conformer, before and after optimization, was carried out at the same level of theory referred above. Characteristic absorption vibrational bands of the spectra of solid pindolol and of the isolated conformer were identified. Intra- and intermolecular interactions in pindolol were confirmed by the frequency shift of the vibrational modes and by the NBO theory. A detailed molecular picture of pindolol and of its intermolecular interactions was obtained from spectroscopy and NBO theory. The combination of both methods gives a deeper insight into the structure.

Solventless metallation of low melting porphyrins synthesized by the water/microwave method

Herein, we unveil a new ecofriendly methodology for the synthesis of low melting point meso-substituted metalloporphyrins. The water/microwave (MW) synthetic method was used to prepare low melting point unsymmetrical meso-aryl substituted porphyrins and meso-alkyl substituted porphyrins, which uses water under MW irradiation, acting as the solvent/acid catalyst/oxidant in sub-critical conditions. A straightforward conceptual method for the preparation of their metal complexes in very high yields, in the absence of either solvent or base was followed. Thermomicroscopy studies were carried out to assess the metallation reaction, showing that the process is a typical solventless reaction. Calculation of sustainability classifications such as E factors and EcoScale values (as low as 283 and as high as 82 respectively, for the metallation procedure) and very favorable EHS classification establishes this methodology as one presenting the best sustainability classification on porphyrin synthesis.

Calorimetric study of polymorphic forms of terfenadine

Abstract Terfenadine polymorphic forms have been prepared by crystallization from ethanol and methanol solutions. The two polymorphs were studied by differential scanning calorimetry (DSC) and thermogravimetry (TG) in a temperature range between 233 and 443 K. From DSC data, structural differences between both forms were pointed out. Enthalpies for solution processes of the polymorphs in ethanol and in methanol were determined. Differences between both solid forms as well as between the solvent behaviour are well noted from the standard solution enthalpy values and from the variation of the enthalpy with concentration.

Resolved structures of two picolinamide polymorphs. Investigation of the dimorphic system behaviour under conditions relevant to co-crystal synthesis

The polymorphism of picolinamide, one of the three isomeric pyridinecarboxamides, a group of co-formers with relevance for co-crystal research, has been investigated. Particular attention has been focused on phase transitions brought about in DSC scanning experiments or during ball mill grinding, a common strategy in co-crystal synthesis. Two polymorphs, which the Burger and Ramberger empirical rules predict to be enantiotropically related, were identified. The crystal structure of the room temperature stable polymorph II, Tfus,II = 102.0 °C, was redetermined, while that of the ambient temperature metastable polymorph I, Tfus,I = 106.4 °C, was determined for the first time. This was produced as single crystals by sublimation in an oven at 90 °C. In the crystalline structure of this polymorphic form, hydrogen bonds link the molecules in tetramers, which are then packed in piles along the a axis in an arrangement that has not been found in any of the previously solved crystalline structures of isomeric pyridinecarboxamides. Hirshfeld surface analysis was performed in order to facilitate comparison of the intermolecular contacts in both polymorphs. Ball mill grinding of commercial polymorph II gives rise to different outcomes, depending on the experimental conditions: neat grinding for 120 minutes results in conversion to polymorph I, while the addition of 10 μL of toluene, ethyl acetate, dimethylsulfoxide, methanol, ethanol or isopropyl alcohol and liquid assisted grinding stabilizes polymorph II.

Synthesis of low melting point porphyrins: A quest for new materials

Preparation of porphyrins which do not aggregate, possessing low melting points is an endearing challenge for several applications in materials science. In this contribution a viewpoint regarding the synthesis of low melting point porphyrins, is presented. Herein we review the synthesis of symmetrical and unsymmetrical substituted porphyrins that hold the possibility to be used in several materials science applications and present new results on the spectroscopic and thermal characterization of some low melting point meso-tetrasubstituted porphyrins.

Melting curves of terfenadine crystallized from different solvents

Several samples of terfenadine prepared by crystallization from different solvents under different experimental conditions were studied. The DSC curves obtained at a heating rate of 1°C min−1 afforded the temperature of melting and the mole fractions of the components of each sample. Certain of the samples were composed of two solid phases mixed in molar ratios varying between nearly one and a single structural form. Three polymorphic forms were identified.

Co-crystals of diflunisal and isomeric pyridinecarboxamides – a thermodynamics and crystal engineering contribution

Diflunisal is an anti-inflammatory, non-steroidal drug, class II of the Biopharmaceutical Classification System, which has recently been the subject of renewed interest due to its potential for use in the oral therapy of familial amyloid polyneuropathy. In this study, a thermodynamics based approach is used to investigate binary mixtures (diflunisal + picolinamide and diflunisal + isonicotinamide) in order to identify solid forms that are potentially useful to improve the biopharmaceutical performance of this active pharmaceutical ingredient. Special emphasis is placed on the research of co-crystals and on the influence of structural changes in the pyridinecarboxamide co-former molecules for co-crystal formation with diflunisal. The thermodynamics based methodology described by ter Horst et al. in 2010 indicates that the formation of co-crystals is thermodynamically feasible for both systems. The binary solid–liquid phase diagrams were built and allowed unequivocal identification of the formation of co-crystals of diflunisal with each of the two isomers and also their stoichiometry of 1 : 1, (diflunisal : co-former) in the case of pyridine-2-carboxamide (picolinamide) and (2 : 1) for pyridine-4-carboxamide (isonicotinamide). Two binary eutectic mixtures, potentially relevant for pharmaceutical application, were also identified. Infrared spectroscopy allowed the identification of the acid⋯N-pyridine heterosynthon in the three co-crystals formed by diflunisal with the isomeric pyridinecarboxamides. However, the results clearly differentiated pyridine-2-carboxamide from pyridine-3-carboxamide and pyridine-4-carboxamide, that share similar crystalline arrangements, at least with respect to the supramolecular synthons.