Rafael Barbas

Oxyma: An Efficient Additive for Peptide Synthesis to Replace the Benzotriazole‐Based HOBt and HOAt with a Lower Risk of Explosion[1]

Oxyma [ethyl 2-cyano-2-(hydroxyimino)acetate] has been tested as an additive for use in the carbodiimide approach for formation of peptide bonds. Its performance in relation to those of HOBt and HOAt, which have recently been reported to exhibit explosive properties, is reported. Oxyma displayed a remarkable capacity to inhibit racemization, together with impressive coupling efficiency in both automated and manual synthesis, superior to those of HOBt and at least comparable to those of HOAt, and surpassing the latter coupling agent in the more demanding peptide models. Stability assays showed that there was no risk of capping the resin under standard coupling conditions. Finally, calorimetry assays (DSC and ARC) showed decomposition profiles for benzotriazole-based additives that were consistent with their reported explosivities and suggested a lower risk of explosion in the case of Oxyma.

New polymorphic hydrogen bonding donor-acceptor system with two temperature coincident solid-solid transitions†

The polymorphism study of dibenzylsquaramide reveals the appearance of two forms sharing a solid–solid transition at the same temperature towards the highest melting polymorph.

Ziprasidone malate, a new trimorphic salt with improved aqueous solubility

A new salt of ziprasidone with high aqueous solubility has been discovered as a result of a salt screening and it has been found to exist in three anhydrous polymorphic forms. One of these forms shows the highest aqueous solubility ever reported for ziprasidone salts in combination with a high kinetic stability, becoming a good candidate for further pharmaceutical development.

Cooperative induction in double H-bonding donor/acceptor compounds: Chains vs. ribbons

Two different types of monodimensional crystalline aggregates formed by squaramides, chains and ribbons, have been studied both in the solid state and ab initio with four model compounds. Although ribbons are a priori possible, only covalently forced syn conformations have been observed. Cooperative induction is postulated to explain the preference for chains instead of ribbons in squaramide crystals.

Water wires in the nanoporous form II of carbamazepine: a single-crystal X-ray diffraction analysis

We report the crystal structure of a new water wire encapsulated inside the channels formed by the hydrophobic aromatic surfaces of carbamazepine. This new example of a water chain increases the scarce collection of structural data in this field and contributes to the understanding of the role of water chains in the stabilization of certain packing motifs.

A cocrystal is the key intermediates for the production of a new polymorph of Vorinostat

A new kinetically stable polymorph of Vorinostat has been discovered as a result of a polymorph screening, however an impurity is always formed in its preparation by crystallization. The interaction of Vorinostat with ammonia yields a new cocrystal which transforms easily through thermal desorption into the new polymorph with a high degree of purity.

The Ca2+–EDTA chelation as standard reaction to validate Isothermal Titration Calorimeter measurements (ITC)

A study about the suitability of the chelation reaction of Ca(2+)with ethylenediaminetetraacetic acid (EDTA) as a validation standard for Isothermal Titration Calorimeter measurements has been performed exploring the common experimental variables (buffer, pH, ionic strength and temperature). Results obtained in a variety of experimental conditions have been amended according to the side reactions involved in the main process and to the experimental ionic strength and, finally, validated by contrast with the potentiometric reference values. It is demonstrated that the chelation reaction performed in acetate buffer 0.1M and 25°C shows accurate and precise results and it is robust enough to be adopted as a standard calibration process.

Polymorphism of (S)-triphenylglycol: kinetic dependent transformation of a new multipolymorphic system

The appearance of six new polymorphic forms of (S)-triphenylglycol and the kinetically dependent transformation observed by DSC by means of quenching from the melt are reported.

Assembling the puzzle of Apixaban solid forms

An in-depth analysis of the solid forms of the anticoagulant drug Apixaban (APX) has been conducted to sort out the confusion in the scientific and patent literature regarding the solid forms landscape. The nomenclature employed and the accompanying characterization data are often unclear and incomplete, leading to a situation in which apparently the same form has been reported by different authors or claimed by different inventors. A comprehensive solid forms screen and a full and careful comparison with the literature data has been performed to draw a reliable picture of the solid forms landscape of APX.

Hydrogen bonding versus π-interactions: their key competition in sildenafil solvates

Herein we report the X-ray characterization of four sildenafil solvates where the conformation of the pyrazolo[3,4-d]pyrimidine and phenyl rings depends on the solvent. It conditions the formation of an apparently innocent intramolecular H-bond that has a remarkable influence on the solid state architecture of the sildenafil solvates. DFT calculations indicate that a delicate balance between the energies of H-bonding and π–π (or lp–π) interactions are crucial.