Polymorphic Ammonium Salts of the Antibiotic 4-Aminosalicylic Acid

Reaction of the antibiotic 4-aminosalicylic acid with ammonia yields three polymorphic forms of the ammonium 4-aminosalicylate salt [NH₄]­[C₆H₃NH₂OH­(COO)]. When the reaction is conducted in solution, the three polymorphs are obtained concomitantly, while liquid-assisted grinding and solid–gas reaction result in the formation of pure Form II. The three polymorphs are characterized by different patterns of hydrogen bonding interactions between the structurally rigid anions and the ammonium cations. Solid products were characterized by single-crystal and powder X-ray diffraction, variable temperature powder diffraction, calorimetric techniques (DSC and TGA), and hot-stage microscopy (HSM)

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 Cu²⁺ 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

Polymorphic Ammonium Salts of the Antibiotic 4-Aminosalicylic Acid

Reaction of the antibiotic 4-aminosalicylic acid with ammonia yields three polymorphic forms of the ammonium 4-aminosalicylate salt [NH₄]­[C₆H₃NH₂OH­(COO)]. When the reaction is conducted in solution, the three polymorphs are obtained concomitantly, while liquid-assisted grinding and solid–gas reaction result in the formation of pure Form II. The three polymorphs are characterized by different patterns of hydrogen bonding interactions between the structurally rigid anions and the ammonium cations. Solid products were characterized by single-crystal and powder X-ray diffraction, variable temperature powder diffraction, calorimetric techniques (DSC and TGA), and hot-stage microscopy (HSM)

Polymorphic Ammonium Salts of the Antibiotic 4-Aminosalicylic Acid

Reaction of the antibiotic 4-aminosalicylic acid with ammonia yields three polymorphic forms of the ammonium 4-aminosalicylate salt [NH₄]­[C₆H₃NH₂OH­(COO)]. When the reaction is conducted in solution, the three polymorphs are obtained concomitantly, while liquid-assisted grinding and solid–gas reaction result in the formation of pure Form II. The three polymorphs are characterized by different patterns of hydrogen bonding interactions between the structurally rigid anions and the ammonium cations. Solid products were characterized by single-crystal and powder X-ray diffraction, variable temperature powder diffraction, calorimetric techniques (DSC and TGA), and hot-stage microscopy (HSM)

New Multicomponent Sulfadimethoxine Crystal Forms: Sulfonamides as Participants in Supramolecular Interactions

Sulfadimethoxine (SDM) cocrystal formation was screened using coformers with cyclic amines, amide, carboxylic acid, and sulfonamide based moieties. Eight new multicomponent crystal forms were obtained by solution crystallization and liquid-assisted grinding techniques, showing a preference for the amine derivatives. Cocrystals were obtained with isonicotinamide (SDM:ISO) and 4,4′-bipyridine (SDM:BIP:ACE; SDM:BIP:H₂O), and molecular salts were synthesized with piperazine (SDM:PIP), 4,4′-trimethylenedipiperidine (SDM:TRI), and 1,4-diazabicyclo­[2.2.2]­octane (two anhydrous polymorphic forms (SDM:DABCO) and one hydrate (SDM:DABCO:H₂O)). The new forms were fully characterized by X-ray diffraction. Structural characterization shows the disruption of the typical <i>R</i>₂²(8) sulfonamide synthon, while the supramolecular arrangement is achieved through several new synthons. In cocrystals, the amide nitrogen N_sulfonamide behaves as the best donor and bonds to the O_acetamide of ISO, while with BIP the interaction is established with the N_BIP atom. In salts, charge assisted hydrogen bonds are established, predominantly with the amide nitrogen, the best acceptor, or the sulfonyl O atom, but there is a strong competition with the N atom of the pyrazine ring (N_pyrazine). Thermal behavior and physicochemical properties were assessed by thermogravimetric analysis, differential scanning calorimetry, variable temperature powder X-ray diffraction, and hot-stage microscopy techniques. As expected, the molecular salts reveal higher solubility in water than the cocrystals, an important aspect for the improvement of SDM performance

Expanding the Pool of Multicomponent Crystal Forms of the Antibiotic 4‑Aminosalicylic Acid: The Influence of Crystallization Conditions

Finding new multicomponent crystal forms of commercially available pharmaceuticals is important, as they represent a straightforward way to drastically influence the solid-state properties of a drug. The antibiotic 4-aminosalicylic acid (ASA) is known to exist in several multicomponent crystal forms, and in this work we expand the world of ASA cocrystals and salts by reporting new crystalline forms comprising diazabicyclo[2.2.2]­octane (DABCO), and caffeine. All species were characterized by X-ray single crystal, powder diffraction, and thermal behavior. This study contributes to the rationalization of preferred functional groups for the synthesis of 4-aminosalicylic acid new multicomponent crystal forms and highlights the relevance of the reaction conditions in the achievement of those forms

Understanding Polymorphic Control of Pharmaceuticals Using Imidazolium-Based Ionic Liquid Mixtures as Crystallization Directing Agents

Imidazolium-based room temperature ionic liquids (RTILs) were tested to assess their ability to control molecular polymorphic behavior. Mixtures of RTILs with distinct cation/anion combinations revealed promising capabilities in directing the crystallization process toward less stable polymorphs. In our tests, gabapentin (GBP) neuroleptic drug was used as a case study, as it is a well know polymorphic active pharmaceutical ingredient. For the first time, pure “bulk” GBP Form IV, a highly unstable polymorph, was isolated through RTILs. Forms were maintained over time, once they were kept soaked, opening new perspectives for the method presented here. Molecular dynamics (MD) simulations clearly supported the results. In this work the polymorphic behavior of GBP is controlled recurring to the use of different pure imidazolium-based RTILs or mixtures, as crystallization solvents. Molecular dynamics simulations clearly supported the results showing that specific H_{(acidic(C4/C6mim))}···O_{(carboxylate)} interaction between GBP and RTILs drives the formation of Form IV. For the first time, pure “bulk” GBP Form IV, a highly unstable polymorph, was isolated. These results showed the importance of these “directing agents” in the polymorphic process as well as the importance of using MD simulations in predicting the “designed” crystallization environment for the “desired” polymorph

Gabapentin Coordination Networks: Mechanochemical Synthesis and Behavior under Shelf Conditions

Active pharmaceutical ingredients (API) coordination complexes and networks present a promising pathway for developing new bioinspired materials. In the present study, we report several coordination networks of gabapentin with Y­(III), Mn­(II), and several lanthanides (LnCl₃), Ln = La³⁺, Ce³⁺, Nd³⁺, Er³⁺ obtained by mechanosynthesis. To the best of our knowledge, these are among the first coordination networks of pharmaceuticals involving lanthanides. These novel compounds proved to be unstable under shelf conditions, are thermally stable until water release at approximately 80 °C, and decompose above 200–250 °C. The coordination networks obtained present different structural architectures based on mono-, di-, tri-, and hexa-metallic centers (herein called monomers, dimers, trimers, and hexamers), and also a one-dimensional polymeric chain was obtained. Gabapentin chelation modes are the same in most of the networks, adopting three typical geometries: the bidentate coordination – chelation, mode I; the bridge coordination, mode II, and the “bidentate-bridge” coordination, mode III. NMR studies show that the compounds have different behavior in solution, where a single coordination mode seems to be present

12,17-Cyclojatrophane and Jatrophane Constituents of <i>Euphorbia welwitschii</i>

Euphowelwitschines A (<b>1</b>) and B (<b>2</b>), isolated from a methanolic extract of <i>Euphorbia welwitschii</i>, exhibit a rare combination of structural features in having a 5/8/8 fused-ring system and a 12,15-ether bridge. Moreover, the isolation of the additional new compounds welwitschene (<b>3</b>) and epoxywelwitschene (<b>4</b>) has provided insights into the biogenetic pathway of 12,17-cyclojatrophanes. The structures of <b>1</b>–<b>4</b> were determined by spectroscopic methods inclusive of 1D and 2D NMR experiments and X-ray crystallography for compounds <b>1</b> and <b>2</b>. Preliminary information on the selective antiproliferative activity of compounds <b>1</b>–<b>4</b> is also described

Toward the Understanding of Radical Reactions: Experimental and Computational Studies of Titanium(III) Diamine Bis(phenolate) Complexes

Radical reactions of titanium­(III) [Ti­(^<i>t</i>Bu2O₂NN′)­Cl­(S)] (S = THF, <b>1</b>; S = py, <b>2</b>; ^<i>t</i>Bu2O₂NN′ = Me₂N­(CH₂)₂N­(CH₂-2-O-3,5-^<i>t</i>Bu₂C₆H₂)₂) are described. Reactions with neutral electron acceptors led to metal oxidation to Ti­(IV), [Ti­(^<i>t</i>Bu2O₂NN′)­Cl­(TEMPO)] (<b>4</b>) being formed with the TEMPO radical and [Ti­(^<i>t</i>Bu2O₂NN′)­Cl₂] (<b>9</b>) with PhNNPh. [Ti­(^<i>t</i>Bu2O₂NN′)­Cl₂] was also formed when [Ti­(^<i>t</i>Bu2O₂NN′)­Cl­(S)] was oxidized by [Cp₂Fe]­[BPh₄], but the [Cp₂Fe]­[PF₆] analogue yielded [Ti­(^<i>t</i>Bu2O₂NN′)­ClF] (<b>8</b>). The reactions of [Ti­(^<i>t</i>Bu2O₂NN′)­Cl­(S)] with O₂ gave [Ti­(^<i>t</i>Bu2O₂NN′)­Cl]₂(μ-O) (<b>3</b>). The DFT calculated Gibbs energy for the above reaction showed it to be exergonic (Δ<i>G</i>₂₉₈ = −123.6 kcal·mol^–1). [Ti­(^<i>t</i>Bu2O₂NN′)­(CH₂Ph)­(S)] (S = THF, <b>5</b>; py, <b>6</b>) are not stable in solution for long periods and in diethyl ether gave 1:1 cocrystals of [Ti­(^<i>t</i>Bu2O₂NN′)­(CH₂Ph)₂] (<b>7</b>) and [Ti­(^<i>t</i>Bu2O₂NN′)­Cl]₂(μ-O) (<b>3</b>), most probably resulting from a disproportionation process of titanium­(III) followed by oxygen abstraction by the resulting Ti­(II) species. The oxidation of [Ti­(^<i>t</i>Bu2O₂NN′)­(κ²-{CH₂-2-(NMe₂)-C₆H₄})] (<b>10</b>), which is a Ti­(III) benzyl stabilized by the intramolecular coordination of the NMe₂ moiety, led to a complex mixture. Recrystallization of this mixture under air led to a 1:1 cocrystal of two coordination isomers of the titanium oxo dimer (<b>3</b>). In one of these isomers, one metal is pentacoordinate and the dimethylamine moiety of the diamine bis­(phenolate) ligand is not bonded to the metal, displaying a coordination mode of the ligand never observed before. The other titanium center is distorted octahedral with two <i>cis</i>-phenolate moieties. In the second unit, the coordination of the two ancillary ligands to the titanium centers reveals mutually <i>cis</i>-phenolate groups in one-half of the molecule and <i>trans</i>-coordinated in the other titanium center, keeping a distorted octahedral environment around each titanium