Exploring the Crystal Structure Landscape of Sulfasalazine through Various Multicomponent Crystals.

Sulfasalazine is used as an anti-inflammatory drug to treat large intestine diseases and atrophic arthritis. In the solid state, two tautomers are known: an amide tautomer (triclinic polymorph) and an imide tautomer (monoclinic polymorph). Crystallization of six new multicomponent solids of sulfasalazine with three cocrystal formers and three salt formers has been achieved by slurry, liquid-assisted grinding and slow evaporation methods. All of the solid forms are characterized by X-ray diffraction techniques, thermal analysis, and Fourier transform infrared spectroscopy. The crystal structural analysis reveals that two sulfasalazine molecules or anions arrange in a head-to-head fashion involving their pyridyl, amide, and sulfonyl groups in an R22(7):R22(8):R22(7) motif. This is the key structural unit appearing in both sulfasalazine imide polymorph and all six multicomponent crystals. In addition, sulfasalazine exists in the amide form in all unsolvated multicomponent crystals obtained in this work and adopts the imide tautomer in the solvated cocrystals and salt. Hirshfeld surface analysis and the associated two-dimensional (2D) fingerprint plots demonstrate that sulfasalazine has significant hydrogen bond donor capability when cocrystallized and is a significant hydrogen bond acceptor in the salts. The frontier molecular orbital analysis indicates that sulfasalazine cocrystals are chemically more stable than the salts.

Experimental and Theoretical Investigation of Hydrogen-Bonding Interactions in Cocrystals of Sulfaguanidine.

Pharmaceutical cocrystals, a type of multicomponent crystalline material incorporating two or more molecular and/or ionic compounds connected by noncovalent interactions (such as hydrogen bonds, π-π interactions, and halogen bonds), are attracting increasing attention in crystal engineering. Sulfaguanidine (SGD), one of the most frequently used sulfonamide compounds, was chosen as a model compound in this work to further investigate the hydrogen bond interactions in cocrystals, since it possesses various hydrogen bond donor and acceptor sites. Five cocrystals of SGD, synthesized successfully by slurry and slow evaporation methods, were fully characterized by thermal analysis, X-ray techniques, and Fourier transform infrared spectroscopy. To gain insight into the nature of hydrogen-bonding interactions, theoretical calculations including the analysis of Hirshfeld surface, MEPS (molecular electrostatic potential surface), and QTAIM (quantum theory of atoms in molecules) were conducted. The results are a part of a systematic study of cocrystals of sulfonamides that aims to establish synthon hierarchies in cocrystals containing molecules with multiple hydrogen-bonding functional groups.

Pharmaceutical Salts of Piroxicam and Meloxicam with Organic Counterions.

Piroxicam (PRM) and meloxicam (MEL) are two nonsteroidal anti-inflammatory drugs, belonging to the Biopharmaceutics Classification System Class II drugs. In this study, six novel pharmaceutical salts of PRM and MEL with three basic organic counterions, that is, 4-aminopyridine (4AP), 4-dimethylaminopyridine (4DMP), and piperazine (PPZ), were prepared by both slurrying and slow evaporation. These salts were characterized by single-crystal and powder X-ray diffraction, thermal analysis, and Fourier transform infrared spectroscopy. All six salts, especially MEL-4DMP and MEL-4AP, showed a significantly improved apparent solubility and dissolution rate in sodium phosphate solution compared with the pure APIs. Notably, PRM-4AP and PRM-4DMP salts exhibited enhanced fluorescence, and the PRM-PPZ salt showed weaker fluorescence compared with that of pure PRM due to different luminescence mechanisms.

Investigating microcrystalline cellulose crystallinity using Raman spectroscopy.

Microcrystalline cellulose (MCC) is a semi-crystalline material with inherent variable crystallinity due to raw material source and variable manufacturing conditions. MCC crystallinity variability can result in downstream process variability. The aim of this study was to develop models to determine MCC crystallinity index (%CI) from Raman spectra of 30 commercial batches using Raman probes with spot sizes of 100 µm (MR probe) and 6 mm (PhAT probe). A principal component analysis model separated Raman spectra of the same samples captured using the different probes. The %CI was determined using a previously reported univariate model based on the ratio of the peaks at 380 and 1096 cm-1. The univariate model was adjusted for each probe. The %CI was also predicted from spectral data from each probe using partial least squares regression models (where Raman spectra and univariate %CI were the dependent and independent variables, respectively). Both models showed adequate predictive power. For these models a general reference amorphous spectrum was proposed for each instrument. The development of the PLS model substantially reduced the analysis time as it eliminates the need for spectral deconvolution. A web application containing all the models was developed. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10570-021-04093-1.

Dirhodium Carboxylate Catalysts from 2-Fenchyloxy or 2-Menthyloxy Arylacetic Acids: Enantioselective C-H Insertion, Aromatic Addition and Oxonium Ylide Formation/Rearrangement.

A new class of dirhodium carboxylate catalysts have been designed and synthesized from 2-fenchyloxy or 2-menthyloxy arylacetic acids which display excellent enantioselectivity across a range of transformations of α-diazocarbonyl compounds. The catalysts were successfully applied to enantioselective C-H insertion reactions of aryldiazoacetates and α-diazo-ß-oxosulfones affording the respective products in up to 93 % ee with excellent trans diastereoselectivity in most cases. Furthermore, efficient desymmetrization in an intramolecular C-H insertion was achieved. In addition, these catalysts prove highly enantioselective for intramolecular aromatic addition with up to 88 % ee, and oxonium ylide formation and rearrangement with up to 74 % ee.

Sounding out falsified medicines from genuine medicines using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS).

The trade in falsified medicine has increased significantly and it is estimated that global falsified sales have reached $100 billion in 2020. The EU Falsified Medicines Directive states that falsified medicines do not only reach patients through illegal routes but also via the legal supply chain. Falsified medicines can contain harmful ingredients. They can also contain too little or too much active ingredient or no active ingredient at all. BARDS (Broadband Acoustic Resonance Dissolution Spectroscopy) harnesses an acoustic phenomenon associated with the dissolution of a sample (tablet or powder). The resulting acoustic spectrum is unique and intrinsic to the sample and can be used as an identifier or signature profile. BARDS was evaluated in this study to determine whether a product is falsified or genuine in a rapid manner and at lower cost than many existing technologies. A range of genuine and falsified medicines, including falsified antimalarial tablets from south-east Asia, were tested, and compared to their counterpart genuine products. Significant differences between genuine and falsified doses were found in their acoustic signatures as they disintegrate and dissolve. Principal component analysis was employed to differentiate between the genuine and falsified medicines. This demonstrates that the tablets and capsules included here have intrinsic acoustic signatures which could be used to screen the quality of medicines.

Ambipolar pentacyclic diamides with interesting electrochemical and optoelectronic properties.

Developing organic semiconductors for organic thin film transistors (OTFT) and optoelectronic applications is a challenge. We developed highly crystalline pentacyclic diimides (3) and (4) which showed good OTFT and OLED potential and energy gaps of 2.60 eV and 2.54 eV. They exhibited interesting photo and eletroluminescence activity. Both compounds showed good quantum yields (0.56 for (3) and 0.60 for (4)).

Tetrel Bonding and Other Non-Covalent Interactions Assisted Supramolecular Aggregation in a New Pb(II) Complex of an Isonicotinohydrazide.

A new supramolecular Pb(II) complex [PbL(NO2)]n was synthesized from Pb(NO3)2, N'-(1-(pyridin-2-yl)ethylidene)isonicotinohydrazide (HL) and NaNO2. [PbL(NO2)]n is constructed from discrete [PbL(NO2)] units with an almost ideal N2O3 square pyramidal coordination environment around Pb(II). The ligand L- is coordinated through the 2-pyridyl N-atom, one aza N-atom, and the carbonyl O-atom. The nitrite ligand binds in a κ2-O,O coordination mode through both O-atoms. The Pb(II) center exhibits a hemidirected coordination geometry with a pronounced coordination gap, which allows a close approach of two additional N-atoms arising from the N=C(O) N-atom of an adjacent molecule and from the 4-pyridyl N-atom from the another adjacent molecule, yielding a N4O3 coordination, constructed from two Pb-N and three Pb-O covalent bonds, and two Pb⋯N tetrel bonds. Dimeric units in the structure of [PbL(NO2)]n are formed by the Pb⋯N=C(O) tetrel bonds and intermolecular electrostatically enforced π+⋯π- stacking interactions between the 2- and 4-pyridyl rings and further stabilized by C-H⋯π intermolecular interactions, formed by one of the methyl H-atoms and the 4-pyridyl ring. These dimers are embedded in a 2D network representing a simplified uninodal 3-connected fes (Shubnikov plane net) topology defined by the point symbol (4∙82). The Hirshfeld surface analysis of [PbL(NO2)] revealed that the intermolecular H⋯X (X = H, C, N, O) contacts occupy an overwhelming majority of the molecular surface of the [PbL(NO2)] coordination unit. Furthermore, the structure is characterized by intermolecular C⋯C and C⋯N interactions, corresponding to the intermolecular π⋯π stacking interactions. Notably, intermolecular Pb⋯N and, most interestingly, Pb⋯H interactions are remarkable contributors to the molecular surface of [PbL(NO2)]. While the former contacts are due to the Pb⋯N tetrel bonds, the latter contacts are mainly due to the interaction with the methyl H-atoms in the π⋯π stacked [PbL(NO2)] molecules. Molecular electrostatic potential (MEP) surface calculations showed marked electrostatic contributions to both the Pb⋯N tetrel bonds and the dimer forming π+⋯π- stacking interactions. Quantum theory of atoms in molecules (QTAIM) analyses underlined the tetrel bonding character of the Pb⋯N interactions. The manifold non-covalent interactions found in this supramolecular assembly are the result of the proper combination of the polyfunctional multidentate pyridine-hydrazide ligand and the small nitrito auxiliary ligand.

The sound of tablets during coating erosion, disintegration, deaggregation and dissolution.

This research aims to address a gap in our understanding of the mechanisms by which pharmaceutical tablets achieve highly reproducible and predictable drug release. The present industrial and regulatory practice is centred around tablet dissolution, i.e. what follows disintegration, yet the vast majority of problems that are found in formulation dissolution testing can be traced back to the erratic disintegration behaviour of the medicinal product. It is only due to the distinct lack of quantitative measurement techniques for disintegration analysis that this situation arises. Current methods involve costly, and time-consuming test equipment, resulting in a need for more simple, green and efficient methods which have the potential to enable rapid development and to accelerate routine solid drug formulation dissolution and disintegration testing. In this study, we present a novel approach to track several sequential tablet dissolution processes, including coating erosion, disintegration, deaggregation and dissolution using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS). BARDS, in combination with minimal usage of UV spectroscopy, can effectively track these processes. The data also show that a solid oral dose formulation has an intrinsic acoustic signature which is specific to the method of manufacture and excipient composition.

Isoquinolinequinone N-oxides as anticancer agents effective against drug resistant cell lines.

The isoquinolinequinone (IQQ) pharmacophore is a privileged framework in known cytotoxic natural product families, caulibugulones and mansouramycins. Exploiting both families as a chemical starting point, we report on the structured development of an IQQ N-oxide anticancer framework which exhibits growth inhibition in the nM range across melanoma, ovarian and leukaemia cancer cell lines. A new lead compound (16, R6 = benzyl, R7 = H) exhibits nM GI50 values against 31/57 human tumour cell lines screened as part of the NCI60 panel and shows activity against doxorubicin resistant tumour cell lines. An electrochemical study highlights a correlation between electropositivity of the IQQ N-oxide framework and cytotoxicity. Adduct binding to sulfur based biological nucleophiles glutathione and cysteine was observed in vitro. This new framework possesses significant anticancer potential.

Desymmetrization by Asymmetric Copper-Catalyzed Intramolecular C-H Insertion Reactions of α-Diazo-ß-oxosulfones.

Effective desymmetrization in copper-catalyzed intramolecular C-H insertion reactions of α-diazo-ß-oxosulfones in the formation of fused thiopyran dioxides is described for the first time. The use of a copper-bis(oxazoline)-NaBARF catalyst complex system leads to formation of the major thiopyran dioxide stereoisomer with up to 98:2 dr and up to 98% ee. The effect of varying the bis(oxazoline) ligand, copper salt, and site of C-H insertion on both diastereo- and enantioselectivities of these intramolecular C-H insertion reactions has been investigated. Similarly, desymmetrization in the formation of a fused cyclopentanone proceeds with up to 64% ee. These results represent the highest enantioselectivity reported to date in a copper-mediated desymmetrization through C-H insertion.

Correction: Enantioselective copper catalysed intramolecular C-H insertion reactions of α-diazo-ß-keto sulfones, α-diazo-ß-keto phosphine oxides and 2-diazo-1,3-diketones; the influence of the carbene substituent.

Correction for 'Enantioselective copper catalysed intramolecular C-H insertion reactions of α-diazo-ß-keto sulfones, α-diazo-ß-keto phosphine oxides and 2-diazo-1,3-diketones; the influence of the carbene substituent' by Amy E. Shiely et al., Org. Biomol. Chem., 2017, 15, 2609-2628.

Synthesis of 1,2,5-oxathiazole-S-oxides by 1,3-dipolar cycloadditions of nitrile oxides to α-oxo sulfines.

Synthetic methodology for the generation of novel 1,2,5-oxathiazole-S-oxides from cycloaddition of nitrile oxide dipoles with α-oxo sulfines generated in situ via the α-sulfinyl carbenes derived from α-diazosulfoxides is described. Experimental evidence and mechanistic rationale for the unanticipated interconversion of the diastereomeric 1,2,5-oxathiazole-S-oxide cycloadducts are discussed. Notably, using rhodium acetate as a catalyst at 0 °C under traditional batch conditions led to the selective formation and isolation of the kinetic isomers, while, in contrast, using continuous flow thermolysis, optimal conditions for the synthesis and isolation of the thermodynamic isomers were established.

Predicting Nucleation of Isonicotinamide from the Solvent-Solute Interactions of Isonicotinamide in Common Organic Solvents.

The interactions of isonicotinamide (INA) with seven common solvents (acetic acid, acetonitrile, acetone, chloroform, ethyl acetate, and methanol) have been studied to examine solute-solvent effects on the nucleation of INA from these solvents. In a simple model of 1:1 solute-solvent interactions, the strongest INA-solvent interaction is with acetic acid (binding energy, Δ Ebind = -64.05 kJ mol-1) and the weakest is with chloroform (Δ Ebind = -24.85 kJ mol-1). This arises since acetic acid and INA form a hydrogen-bonding motif containing two moderate strength N-H···O hydrogen bonds, while chloroform and INA have a single weak C-H···O hydrogen bond. Taking acetic acid, chloroform, and methanol, the solvents with the strongest, the weakest, and an intermediate strength INA-solvent binding energy, the solvation of INA was studied to compare it with the 1:1 model. Acetic acid has the strongest binding energy (-872.24 kJ mol-1) and solvation energy (-341.20 kJ mol-1) with chloroform binding energy (-517.72 kJ mol-1) and solvation energy (-199.05 kJ mol-1). Methanol has intermediate binding energy (-814.19 kJ mol-1) and solvation energies (-320.81 kJ mol-1). These results further confirm the recent the findings which indicate that the key trends in solvent-solute interactions can be determined from a simple and efficient 1:1 dimer model and can be used to predict ease of nucleation with stronger binding energies correlating to slower, more difficult nucleation. A limit of this model is revealed by considering alcohol and acid solvents with longer alkyl chains.

Synthesis and Antiproliferative Activity of Novel Heterocyclic Indole-Trimethoxyphenyl Conjugates.

The synthesis and biological evaluation of a series of novel heterocyclic indole derivatives is described. The consolidation of the combretastatin and bisindolylmaleimide templates towards the inclusion of a novel heterocyclic ring proffered a versatile pharmacophore with which to pursue chemical diversification. Given literature precedent, maleimide was initially investigated in this role and the bioactivity assessed by measurement of NCI-60 cell panel growth. Subsequently, a range of 5-aminopyrazoles was designed and developed to explore the specific effect of heterocycle hydrogen bonding on cell growth. The unique electronic nature of the 5-aminopyrazole moiety allowed for regiospecific monosubstitution on different sites of the ring, such as thiourea substitution at the N(1) position for derivative 45 or trifluoroacetylation on the 5-amino position for 43. Further derivatisation led to the ultimate development of bicyclic pyrazolotriazinedione 41 and pyrimidine 42 systems. The antiproliferative activities of these 3,4-diaryl-5-aminopyrazoles were assessed using the NCI-60 cell screen, disclosing the discovery of distinct selectivity profiles towards a number of cell lines, such as SNB-75 CNS cancer, UO-31 and CAKI-1 renal cancer cells. A series of DNA topological assays discounted the interaction with topoisomerase II as a putative mechanism of action.

Symmetry assisted tuning of bending and brittle multi-component forms of probenecid.

The mechanical flexibility known in the antihyperuricemia drug probenecid has been extended into multi-component systems using co-formers with two donor or acceptor sites, in contrast to systems with a single H-bond acceptor that exhibit brittle behaviour. The piperazinium salt demonstrates that GRAS co-formers can be used to maintain mechanical flexibility with drug molecules.

Synthesis of Cyclic α-Diazo-ß-keto Sulfoxides in Batch and Continuous Flow.

Diazo transfer to ß-keto sulfoxides to form stable isolable α-diazo-ß-keto sulfoxides has been achieved for the first time. Both monocyclic and benzofused ketone derived ß-keto sulfoxides were successfully explored as substrates for diazo transfer. Use of continuous flow leads to isolation of the desired compounds in enhanced yields relative to standard batch conditions, with short reaction times, increased safety profile, and potential to scale up.

Enantioselective copper catalysed intramolecular C-H insertion reactions of α-diazo-ß-keto sulfones, α-diazo-ß-keto phosphine oxides and 2-diazo-1,3-diketones; the influence of the carbene substituent.

Enantioselectivities in C-H insertion reactions, employing the copper-bis(oxazoline)-NaBARF catalyst system, leading to cyclopentanones are highest with sulfonyl substituents on the carbene carbon, and furthermore, the impact is enhanced by increased steric demand on the sulfonyl substituent (up to 91%ee). Enantioselective intramolecular C-H insertion reactions of α-diazo-ß-keto phosphine oxides and 2-diazo-1,3-diketones are reported for the first time.

Exploring the Scope of Asymmetric Synthesis of ß-Hydroxy-γ-lactams via Noyori-type Reductions.

Enantio- and diastereoselective hydrogenation of ß-keto-γ-lactams with a ruthenium-BINAP catalyst, involving dynamic kinetic resolution, has been employed to provide a general, asymmetric approach to ß-hydroxy-γ-lactams, a structural motif common to several bioactive compounds. Full conversion to the desired ß-hydroxy-γ-lactams was achieved with high diastereoselectivity (up to >98% de) by addition of catalytic HCl and LiCl, while ß-branching of the ketone substituent demonstrated a pronounced effect on the modest to excellent enantioselectivity (up to 97% ee) obtained.

Diversity in a simple co-crystal: racemic and kryptoracemic behaviour.

The crystal structure containing (±)-3-methyl-2-phenylbutyramide with salicylic acid is the first example of a kryptoracemate co-crystal. It exhibits the first temperature mediated reversible single-crystal to single-crystal transition between two kryptoracemate forms, in addition to crystallising in another, racemic, form. Theoretical calculations and structural analysis reveal that there are only small differences in both energy and packing arrangements between the three forms. These results suggest that co-crystals can be an opportunity to investigate kryptoracemate behaviour.