Vânia André

Mechanosynthesis of the Metallodrug Bismuth Subsalicylate from Bi2O3 and Structure of Bismuth Salicylate without Auxiliary Organic Ligands

Mechanochemical reactions are versatile for the synthesis of new pharmaceutical forms, particularly cocrystals, salts and, since very recently, coordination complexes. Mechanochemistry can be very efficient for the synthesis of metal–organic frameworks (MOFs) and magnesium-based pharmaceuticals directly from inexpensive and otherwise inert materials, such as metal oxides or carbonates. In addition to short reaction times and the lack of bulk solvents, oxide-based mechanosynthesis also has the advantage of generating water as the sole byproduct. We now demonstrate how ionand liquid-assisted grinding (ILAG), previously utilized for the mechanosynthesis of large-pore MOFs and zeolitic imidazolate frameworks 6] based on zinc, can be extended to the pharmaceutical chemistry of bismuth oxide. We demonstrate the rapid and efficient conversion of Bi2O3 into a variety of bismuth salicylate complexes, including the commercial active pharmaceutical ingredient (API) bismuth subsalicylate (1), marketed under the trade name Pepto-Bismol. The pharmaceutical value of bismuth complexes with salicylic acid (H2sal) has been established over a century ago and still remains an area of active research. At least three different forms of bismuth salicylate, which differ in the stoichiometric ratio of bismuth and H2sal, have been reported. These are the API bismuth subsalicylate BiO(Hsal), the disalicylate (2) with assigned formula Bi2O(Hsal)4, [8] and the trisalicylate (3) involving bismuth and salicylic acid in the 1:3 stoichiometric ratio. Until now, the structure for any of these materials has remained unknown. Models for 1 and its biological activity were initially devised by Thurston et al. who used auxiliary chelating ligands to trap discrete oligonuclear clusters of Bi and salicylate anions (Hsal ), and by Burford et al. who explored complexation of Bi with thiosalicylic acid. The potential of mechanochemistry to generate bismuth carboxylates was revealed by Andrews and co-workers, 12] who investigated combined mechanoand thermochemical routes involving carboxylic acids and triphenylbismuth. With H2sal this approach provides different organobismuth salicylates unless the ratio of Bi to acid is 1:3, in which case it leads to the tricarboxylate 3 (Figure 1a). Recrystallization of 3 from acetone yielded metal–organic clusters containing coordinated solvent that are currently the best models for the structure of 1 (Figure 1b). Unfortunately, this synthetic pathway is of limited use due to regulatory aspects of organobismuth precursor and the formation of aromatic hydrocarbon byproducts.

Polymorphic gabapentin: thermal behaviour, reactivity and interconversion of forms in solution and solid-state

The various crystal forms of the neuroleptic drug gabapentin have been investigated, and in some cases re-investigated, by a combination of differential scanning calorimetry, hot stage microscopy and variable temperature powder diffraction methods in order to establish the relative stability of both its anhydrous and hydrated forms. A series of steps involving slurrying, heating, de-hydration and reaction with vapours of HCl have been performed. In this latter case, it has been possible to show that the reaction with HCl vapour leads to the same product as that obtained in solution. In slurry experiments in the absence of water, the most stable form, Form II, is invariably obtained, whereas in water, the slurry leads to the conversion of all crystal forms to the hemihydrated Form I. The conditions for the solid-state formation of the gabapentin-lactam de-hydration product have been analysed. Co-crystal formation has also been attempted. In the course of one such experiment, 1 : 1 co-crystals of gabapentin-lactam and benzoic acid were obtained.

Drug-containing coordination and hydrogen bonding networks obtained mechanochemically

In this communication we describe the solid-state preparation and structural characterization of the coordination and hydrogen bonding networks formed by the antibiotic 4-aminosalicylic acid and the nootropic drug piracetam with silver and nickel cations, respectively; the silver complex formed via solid-state reaction is anhydrous, while from solution its hydrated phase is obtained.

New forms of old drugs: improving without changing

In a short approach, we want to present the improvements that have recently been done in the world of new solid forms of known active pharmaceutical ingredients (APIs). The different strategies will be addressed, and successful examples will be given.

Copper(II) Coordination Polymers Self-Assembled from Aminoalcohols and Pyromellitic Acid: Highly Active Precatalysts for the Mild Water-Promoted Oxidation of Alkanes

Three novel water-soluble 2D copper(II) coordination polymers-[{Cu2(μ2-dmea)2(H2O)}2(μ4-pma)]n·4nH2O (1), [{Cu2(μ2-Hedea)2}2(μ4-pma)]n·4nH2O (2), and [{Cu(bea)(Hbea)}4(μ4-pma)]n·2nH2O (3)-were generated by an aqueous medium self-assembly method from copper(II) nitrate, pyromellitic acid (H4pma), and different aminoalcohols [N,N-dimethylethanolamine (Hdmea), N-ethyldiethanolamine (H2edea), and N-benzylethanolamine (Hbea)]. Compounds 2 and 3 represent the first coordination polymers derived from H2edea and Hbea. All the products were characterized by infrared (IR), electron paramagnetic resonance (EPR), and ultraviolet-visible light (UV-vis) spectroscopy, electrospray ionization-mass spectroscopy (ESI-MS(±)), thermogravimetric and elemental analysis, and single-crystal X-ray diffraction (XRD), which revealed that their two-dimensional (2D) metal-organic networks are composed of distinct dicopper(II) or monocopper(II) aminoalcoholate units and μ4-pyromellitate spacers. From the topological viewpoint, the underlying 2D nets of 1-3 can be classified as uninodal 4-connected layers with the sql topology. The structures of 1 and 2 are further extended by multiple intermolecular hydrogen bonds, resulting in three-dimensional (3D) hydrogen-bonded networks with rare or unique topologies. The obtained compounds also act as highly efficient precatalysts for the mild homogeneous oxidation, by aqueous H2O2 in acidic MeCN/H2O medium, of various cycloalkanes to the corresponding alcohols and ketones. Overall product yields up to 45% (based on cycloalkane) were attained and the effects of various reaction parameters were investigated, including the type of precatalyst and acid promoter, influence of water, and substrate scope. Although water usually strongly inhibits the alkane oxidations, a very pronounced promoting behavior of H2O was detected when using the precatalyst 1, resulting in a 15-fold growth of an initial reaction rate in the cyclohexane oxidation on increasing the amount of H2O from ∼4 M to 17 M in the reaction mixture, followed by a 2-fold product yield growth.

Dinuclear Zinc(II) Macrocyclic Complex as Receptor for Selective Fluorescence Sensing of Pyrophosphate

A new diethylenetriamine-derived macrocycle known as L, bearing 2-methylquinoline arms and containing m-xylyl spacers, was prepared in good yield by a one-pot [2 + 2] Schiff base condensation procedure, followed by reduction with sodium borohydride. Up to now this is the first hexaazamacrocycle with appended fluorophore units. Single-crystal X-ray diffraction determination of the dinuclear zinc(II) complex of L showed that metal centers are located at about 7.20(2) Å from one another. This complex exhibits only weak fluorescence in aqueous solution, but the addition of 1 equiv of pyrophosphate (PPi) caused a 21-fold enhancement of the fluorescence intensity. The sensor response is linear up to a value of 10 μM HPPi(3-) and has a detection limit of 300 nM. The receptor behaves as a highly selective sensor for pyrophosphate as other anions, including phosphate, phenylphosphate (PhP), adenosine monophosphate (AMP), adenosine diphosphate (ADP), and adenosine triphosphate (ATP), failed to induce any fluorescence change and practically do not affect the fluorescence intensity of the sensor in the presence of HPPi(3-). Competition titrations carried out in aqueous solution at pH 7.4 [in 20 mM 3-(N-morpholino)propanesulfonic acid (MOPS) buffer] by spectrofluorometry revealed a high association constant value of 6.22 log units for binding of PPi by the dinuclear zinc(II) receptor, one of the highest reported values for colorimetric/fluorometric sensors able to work under real aqueous physiological conditions, while association constant values for binding of the other phosphorylated substrates are in the 5.51-4.03 log unit range.

New tricopper(II) cores self-assembled from aminoalcohol biobuffers and homophthalic acid: synthesis, structural and topological features, magnetic properties and mild catalytic oxidation of cyclic and linear C5–C8 alkanes

Two new crystalline materials [Cu3(μ2-H3bis-tris)2(μ2-Hhpa)2]·H2O (1) and [Cu3(μ2-H2tea)2(μ2-hpa)(μ3-hpa)]n (2) bearing distinct tricopper(II) cores were easily generated by the aqueous medium self-assembly method from copper(II) nitrate, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane (H5bis-tris) or triethanolamine (H3tea) aminoalcohol biobuffers and homophthalic acid (H2hpa). The obtained products were characterised by IR, UV-vis and EPR spectroscopy, ESI-MS(±), thermogravimetric, elemental and single crystal X-ray diffraction analysis. Apart from possessing different dimensionality, the crystal structures of the discrete 0D trimer 1 and the zigzag 1D coordination polymer 2 show distinct symmetric [Cu3(μ-O)4(μ-COO)2] and asymmetric [Cu3(μ-O)3(μ-COO)2] tricopper(II) cores, respectively. An intense pattern of intermolecular O–H⋯O hydrogen bonds provides a 0D → 3D (1) or 1D → 2D (2) extension of the structures into intricate topologically unique H-bonded nets. After additional simplification, these were classified as a uninodal 6-connected 3D framework with the snk topology in 1 and a binodal 3,5-connected 2D layer with the 3,5L50 topology in 2. Variable-temperature magnetic susceptibility studies indicate a predominant ferromagnetic coupling [J = 39.1(1) and 29.5(1) cm−1 for 1 and 2, respectively] within the mixed-bridged tricopper(II) cores. Both compounds 1 and 2 were also applied as rather efficient bio-inspired pre-catalysts for the mild homogeneous oxidation, by aqueous H2O2 at 50 °C in acidic MeCN–H2O medium, of cyclic (cyclopentane, cyclohexane, cycloheptane and cyclooctane) and linear (n-pentane, n-hexane, n-heptane and n-octane) alkanes to the corresponding alcohols and ketones with overall yields up to 26% based on the alkane. The effects of different reaction parameters (type of pre-catalyst and acid promoter, reaction time and substrate scope) and various selectivity features were investigated and discussed, supporting a free-radical mechanism in the present alkane oxidations.

Tailoring aqueous solubility of a highly soluble compound via cocrystallization: effect of coformer ionization, pHmax and solute–solvent interactions

Cocrystals of a nonionizable, water soluble compound (gababentin lactam (GBPL)) with less soluble coformers, are shown to be 2 to 17 times less soluble than GBPL. Cocrystals of GBPL with gentisic acid, 4-hydroxybenzoic acid, 4-aminobenzoic acid and fumaric acid are characterized by carboxylic acid---amide hydrogen bonds between coformer and GBPL, consistent with a previously reported structure of a benzoic acid cocrystal. The lattice and solvation contributions to cocrystal aqueous solubility were evaluated and solvation was found to be the main contribution to solubilization. Cocrystals exhibited pH-dependent solubility and pHmax, both of which are described by coformer pKa and cocrystal Ksp values. These findings have important implications for the characterization and selection of cocrystals for desired drug delivery behavior.

Dicarboxylate Recognition Properties of a Dinuclear Copper(II) Cryptate

A ditopic polyamine macrobicyclic compound with biphenylmethane spacers was prepared, and its dinuclear copper(II) complex was studied as a receptor for the recognition of dicarboxylate anions of varying chain length in H2O/MeOH (50:50 (v/v)) solution. The acid-base behavior of the compound, the stability constants of its complexes with Cu(2+) ion, and the association constants of the copper(II) cryptate with succinate (suc(2-)), glutarate (glu(2-)), adipate (adi(2-)), and pimelate (pim(2-)) were determined by potentiometry at 298.2 ± 0.1 K in H2O/MeOH (50:50 (v/v)) and at ionic strength 0.10 ± 0.01 M in KNO3. The association constants of the same cryptate as receptor for aromatic dicarboxylate substrates, such as phthalate (ph(2-)), isophthalate (iph(2-)), and terephthalate (tph(2-)), were determined through competition experiments by spectrophotometry in the UV region. Remarkably high values of association constants in the range of 7.34-10.01 log units were found that are, to the best of our knowledge, the highest values of association constants reported for the binding of dicarboxylate anions in aqueous solution. A very well defined peak of selectivity was observed with the binding constant values increasing with the chain length and reaching the maximum for substrates with four carbon atoms between the carboxylate groups. Single-crystal X-ray diffraction determinations of the cascade complexes with adi(2-) and tph(2-) assisted in the understanding of the selectivity of the cryptate toward these substrates. The Hirshfeld surface analyses of both cascade complexes suggest that the establishment of several van der Waals interactions between the substrates and the walls of the receptor also contributes to the stability of the associations.

Four-Component Assembly of Chiral N–B Heterocycles with a Natural Product-Like Framework

The dative N-B bond was used to simply assemble heterocycles with a skeleton akin to the 5-oxofuro[2,3-b]furan motif. Twenty-five new N-B heterocycles were prepared via a highly efficient one-pot four-component reaction in yields and diastereoselectivities up to 95% and >97%, respectively. Several reaction intermediates were discovered using electrospray ionization mass spectroscopy which set the basis for the mechanism elucidation using DFT calculations.