Three Polymorphic Forms of Ciprofloxacin Maleate: Formation Pathways, Crystal Structures, Calculations, and Thermodynamic Stability Aspects

Polymorphism of the pharmaceutical salt of ciprofloxacin with maleic acid has been investigated. Ciprofloxacin maleate was found to exist in three polymorphic forms and one hydrate. The formation pathways of the salt polymorphs were elucidated by using solvent screening of the mechanochemical synthesis. It has been found that the mechanochemical reaction of the salt formation consists of two steps, including the formation of a kinetic polymorph as a transitional stage and its conversion into a thermodynamically favorable form. The thermodynamic relationships between the polymorphs were rationalized based on solubility and solution calorimetry measurements. The pattern of intermolecular interactions and crystal lattice energies of the polymorphs were quantified by solid-state density functional theory followed by Bader analysis of periodic electron density

Hydrogen Bond Donor/Acceptor Ratios of the Coformers: Do They Really Matter for the Prediction of Molecular Packing in Cocrystals? The Case of Benzamide Derivatives with Dicarboxylic Acids

Seven new 4-aminobenzamide cocrystals/salts with dicarboxylic acids and one 4-hydroxybenzamide/malonic acid 1:1 cocrystal have been obtained and characterized. Analysis of the Cambridge Structural Database of para-substituted benzamide derivatives cocrystals with dicarboxylic acids has been carried out to understand the influence of hydrogen bond donor/acceptor ratios of the coformers on molecular packing similarity in cocrystals. The concept of supramolecular constructs has been used to compare 37 benzamide derivatives cocrystals/salts. Common zero- to three-dimensional structure fragments have been identified and discussed. Two types of zero-dimensional and two types of one-dimensional fragments of closely para-substituted benzamide derivatives have been identified as the dominating motifs. It has been identified that a deviation from the ratio of hydrogen bond donors and acceptors in cocrystal formers increases the probability of formation of multicomponent crystal solvates. In a number of groups of similarly packed crystals, the minimal values of dissimilarity index X (which means maximal likelihood) are observed for the pairs of structures with halogen-substituted benzamide cocrystals. This study is helpful for understanding cocrystal formation mechanisms and has a high significance for crystal engineering

New Solid Forms of the Antiviral Drug Arbidol: Crystal Structures, Thermodynamic Stability, and Solubility

Salts of the antiviral drug Arbidol (umifenovir) with pharmaceutically relevant benzoate and salicylate anions were obtained, and their crystal structures were described. For Arbidol salicylate, an unstable solvate with acetonitrile was also found and characterized. Analysis of the conformational preferences of the Arbidol molecule in the crystal structures showed that it adopts two types of conformations, namely “open” and “closed”, both of which correspond to local conformational energy minima of the isolated molecule. Thermal stability of the Arbidol salicylate solvates with chloroform and acetonitrile was analyzed by means of differential scanning calorimetry and thermogravimetric analysis. The standard thermodynamic functions of the salt formation were determined. The Gibbs energy change of the process was found to be negative, indicating that the formation of the salts from individual components is a spontaneous process. The dissolution study of the Arbidol salts performed in aqueous buffer solutions with pH 1.2 and 6.8 showed that both salts dissolve incongruently to form an Arbidol hydrochloride monohydrate at pH 1.2 and an Arbidol base at pH 6.8, respectively

5-Methoxy-Substituted Zirconium Bis-indenyl <i>ansa</i>-Complexes: Synthesis, Structure, and Catalytic Activity in the Polymerization and Copolymerization of Alkenes

A number of 2-methyl-4-aryl-5-methoxy-6-alkylindenes and <i>C</i>₂-symmetric Me₂Si-bridged <i>ansa</i>-zirconocenes based on them were synthesized. Zirconocenes were obtained by means of highly effective and scalable racemo-selective synthetic approach based on the use of a Zr <i>tert</i>-butyl amide complex. The structure of μ-(bis-[η⁵-6-<i>tert</i>-butyl-5-methoxy-2-methyl-4-<i>tert</i>-butylphenyl-1<i>H</i>-inden-1-yl]­dimethylsilanediyl)­dichlorozirconium­(IV) (<b>14</b>) has been established with X-ray analysis. The introduction of a methoxy group into the indenyl fragment of zirconocene significantly improved its catalytic performance (i.e., its activity, stereoselectivity, molecular mass potential, and thermal stability) in the polymerization and copolymerization of propylene in comparison with the benchmark Spaleck-zirconocene. The role of the methoxy group is proposed to stabilize the cationic catalytic intermediates, which was confirmed using DFT calculations

Novel Effective Racemoselective Method for the Synthesis of <i>ansa</i>-Zirconocenes and Its Use for the Preparation of <i>C</i>₂-Symmetric Complexes Based on 2-Methyl-4-aryltetrahydro(<i>s</i>)indacene as Catalysts for Isotactic Propylene Polymerization and Ethylene–Propylene Copolymerization

A general and effective method for the racemoselective synthesis of bis-indenyl-type <i>ansa</i>-zirconocenes was proposed and successfully applied for the synthesis of several <i>C</i>₂-symmetric <i>ansa</i>-zirconocenes based on 2-methyl-4-aryltetrahydro-<i>s</i>-indacene. This new racemoselective method relies on ZrCl₃NH-<i>tert</i>-Bu as a key reagent. The formation of racemic products was confirmed by NMR studies and single-crystal X-ray diffraction. The novel complexes are potent catalysts for isotactic propylene polymerization and ethylene–propylene copolymerization

Pharmaceutical Salts of Biologically Active Hydrazone Compound Salinazid: Crystallographic, Solubility, and Thermodynamic Aspects

The crystal structures of salts of the active pharmaceutical ingredient (API) called salinazid with dicarboxylic acids and acesulfame were determined by single-crystal X-ray diffraction method. The crystals contain hydrogen bond motifs of different structure and complexity, the energies of which were estimated by using the quantum theory of atoms in molecules and crystals (QTAIMC) methodology. It was found that the driving force for facile the oxalate and malate salts formation is the bifurcated N⁺–H···O^– and N⁺–H···O hydrogen bond synthon, while salinazid malonate is mainly stabilized via a “classic” pyridinium-carboxylate heterosynthon. The oxalate and acesulfame salts of salinazid were found to be stable during aqueous dissolution experiments, providing a substantial solubility improvement compared to pure API (33 and 18 times, respectively). However, the malonate and malate salts dissolved incongruently and rapidly underwent a solution-mediated transformation to form pure salinazid. Based on the solubility data of the stable salts and of the pure components, the Gibbs free energy of the salts formation were calculated to be −21.2 kJ·mol^–1 for salinazid oxalate and −22.6 kJ·mol^–1 for salinazid acesulfame

Peroxosolvates: Formation Criteria, H₂O₂ Hydrogen Bonding, and Isomorphism with the Corresponding Hydrates

The Cambridge Structural Database has been used to investigate the detailed environment of H₂O₂ molecules and hydrogen-bond patterns within “true” peroxosolvates in which the H₂O₂ molecules do not interact directly with the metal atoms. A study of 65 crystal structures and over 260 hydrogen bonds reveals that H₂O₂ always forms two H-bonds as proton donors and up to four H-bonds as a proton acceptor, but the latter can be absent altogether. The necessary features of peroxosolvate coformers are clarified. (1) Coformers should not participate in redox reactions with H₂O₂ and should not catalyze its decomposition. (2) Coformers should be Brønsted bases or exhibit amphoteric properties. The efficiency of the proposed criteria for peroxosolvate formation is illustrated by the synthesis and characterization of several new crystals. Conditions preventing the H₂O₂/H₂O isomorphous substitution are essential for peroxosolvate stability: (1) Every H₂O₂ in the peroxosolvate has to participate in five or six hydrogen bonds. (2) The distance between the two proton acceptors forming H-bonds with the H₂O₂ molecule should be longer than the distance defined by the nature of the acceptor atoms

Influence of Secondary Interactions on the Structure, Sublimation Thermodynamics, and Solubility of Salicylate:4-Hydroxybenzamide Cocrystals. Combined Experimental and Theoretical Study

Cocrystal screening of 4-hydroxy­benzamide with a number of salicylates (salicylic acid, SA; 4-amino­salicylic acid, PASA; acetyl­salicylic acid, ASA; and salicyl­salicylic acid, SSA) was conducted to confirm the formation of two cocrystals, [SA+4-OHBZA] (1:1) and [PASA+4-OHBZA] (1:1). Their structures were determined using single-crystal X-ray diffraction, and the hydrogen-bond network topology was studied. Thermodynamic characteristics of salicylic acid cocrystal sublimation were obtained experimentally. It was proved that PASA cocrystallization with 4-OHBZA makes the drug more stable and prevents the irreversible process of decarboxylation of PASA resulting in formation of toxic 3-amino­phenol. The pattern of non-covalent interactions in the cocrystals is described quantitatively using solid-state density functional theory followed by Bader analysis of the periodic electron density. It has been found that the total energy of secondary interactions between synthon atoms and the side hydroxyl group of the acid molecule in [SA+4-OHBZA] (1:1) and [PASA+4-OHBZA] (1:1) cocrystals is comparable to the energy of the primary acid–amide hetero­synthon. The theoretical value of the sublimation enthalpy of [SA+4-OHBZA], 231 kJ/mol, agrees fairly well with the experimental one, 272 kJ/mol. The dissolution experiments with [SA+4-OHBZA] have proved that the relatively large cocrystal stability in relation to the stability of its components has a negative effect on the dissolution rate and equilibrium solubility. The [PASA+4-OHBZA] (1:1) cocrystal showed an enhancement of apparent solubility compared to that of the corresponding pure active pharmaceutical ingredient, while their intrinsic dissolution rates are comparable

Weak Interactions Cause Packing Polymorphism in Pharmaceutical Two-Component Crystals. The Case Study of the Salicylamide Cocrystal

Two polymorphs of the salicylamide cocrystal with oxalic acid have been obtained and described. Form I of the cocrystal was prepared by three alternative methods in various solvents, while formation of form II was achieved only by a special crystallization procedure. Single-crystal X-ray analysis has revealed that polymorphs consist of conformationally identical salicylamide and oxalic acid molecules, which are assembled into supramolecular units connected via a network of very similar hydrogen bonds. The packing arrangements of the cocrystal polymorphs, however, were found to be different, suggesting a rare example of packing polymorphism. The stability relationship between the polymorphs has been rationalized by using a number of experimental methods, including thermochemical analysis, solubility, and solution calorimetry measurements. Similarities and differences in intermolecular contacts across two polymorphs have been visualized using the Hirshfeld surface analysis. The Bader analysis of the theoretical electron density has enabled us to quantify the pattern of noncovalent interactions in the considered cocrystals. Applicability of different theoretical schemes for evaluation of the lattice energy of the two-component organic crystals has been discussed

N,O-ditosylethanolamine as effective reagent for the synthesis of heterocyclic tertiary amine salts

<p>During the synthesis of N-tosylaziridine, two unexpected products were isolated: 1-(2-(p-tolylsulfonamido)ethyl)pyridinium p-tolylsulfonate (<b>3</b>) and N,N,O-tri-(p-tolylsulfonyl)ethanolamine (<b>3a</b>). The structures of <b>3</b> and <b>3a</b> were investigated in solid state by X-ray analysis. A new family of related salts was obtained using an efficient and facile one-pot synthesis consisting in the interaction between various nitrogen heterocycles and N,O-ditosylethanolamine.</p