A molecularly enhanced proof of concept for targeting cocrystals at molecular scale in continuous pharmaceuticals cocrystallization.

It is impossible to optimize a process for a target drug product with the desired profile without a proper understanding of the interplay among the material attributes, the process parameters, and the attributes of the drug product. There is a particular need to bridge the micro- and mesoscale events that occur during this process. Here, we propose а molecular engineering methodology for the continuous cocrystallization process, based on Raman spectra measured experimentally with a probe and from quantum mechanical calculations. Using molecular dynamics simulations, the theoretical Raman spectra were calculated from first principles for local mixture structures under an external shear force at various temperatures. A proof of concept is developed to build the process design space from the computed data. We show that the determined process design space provides valuable insight for optimizing the cocrystallization process at the nanoscale, where experimental measurements are difficult and/or inapplicable. The results suggest that our method may be used to target cocrystallization processes at the molecular scale for improved pharmaceutical synthesis.

Mechanochemical synthesis of novel metronidazole cocrystal: Structure characterization and pharmaceutical properties study.

A new cocrystalline form of metronidazole (MET) with propyl gallate (PRO), referred to as MET-PRO, has been successfully synthesized and characterized. Structural characterization reveals that MET and PRO are present in a 1:1 ratio within the cocrystal lattice, with one water molecule equivalent incorporated into the structure. This arrangement facilitates the formation of MET-PRO heterodimers and multiple stable units, collectively constructing a three-dimensional supramolecular network. The solubility and permeability of the current cocrystal, along with the parent drug MET, are evaluated under physiological pH conditions. Experimental findings reveal that MET within the cocrystal exhibits a 1.54-2.37 folds increase in solubility and approximately a threefold improvement in permeability compared to its standalone form. Intriguingly, these concurrent enhancements in the physicochemical properties of MET lead to augmented antibacterial activity in vitro, evidenced by a reduction in minimum inhibitory concentration. Even more intriguingly, the enhanced physicochemical properties observed in vitro for the current cocrystal translate into tangible pharmacokinetic benefits in vivo, characterized by prolonged half-life and enhanced bioavailability. Consequently, this research not only introduces a fresh crystal structure for antibacterial medication but also presents approach for optimizing drug properties across in vitro and in vivo settings, while concurrently bolstering the antibacterial effectiveness of MET through pharmaceutical cocrystallization techniques.

Highly Soluble Dacarbazine Multicomponent Crystals Less Prone to Photodegradation.

Dacarbazine (DTIC) is a widely prescribed oncolytic agent to treat advanced malignant melanomas. Nevertheless, the drug is known for exhibiting low and pH-dependent solubility, in addition to being photosensitive. These features imply the formation of the inactive photodegradation product 2-azahypoxanthine (2-AZA) during pharmaceutical manufacturing and even drug administration. We have focused on developing novel DTIC salt/cocrystal forms with enhanced solubility and dissolution behaviors to overcome or minimize this undesirable biopharmaceutical profile. By cocrystallization techniques, two salts, two cocrystals, and one salt-cocrystal have been successfully prepared through reactions with aliphatic carboxylic acids. A detailed structural study of these new multicomponent crystals was conducted using X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR and 1H NMR), and thermal (TG and DSC) analyses. Most DTIC crystal forms reported display substantial enhancements in solubility (up to 19-fold), with faster intrinsic dissolution rates (from 1.3 to 22-fold), contributing positively to reducing the photodegradation of DTIC in solution. These findings reinforce the potential of these new solid forms to enhance the limited DTIC biopharmaceutical profile.

Optimizing Drug Development: Harnessing the Sustainability of Pharmaceutical Cocrystals.

Environmental impacts of the industrial revolution necessitate adoption of sustainable practices in all areas of development. The pharmaceutical industry faces increasing pressure to minimize its ecological footprint due to its significant contribution to environmental pollution. Over the past two decades, pharmaceutical cocrystals have received immense popularity due to their ability to optimize the critical attributes of active pharmaceutical ingredients and presented an avenue to bring improved drug products to the market. This review explores the potential of pharmaceutical cocrystals as an ecofriendly alternative to traditional solid forms, offering a sustainable approach to drug development. From reducing the number of required doses to improving the stability of actives, from eliminating synthetic operations to using pharmaceutically approved chemicals, from the use of continuous and solvent-free manufacturing methods to leveraging published data on the safety and toxicology, the cocrystallization approach contributes to sustainability of drug development. The latest trends suggest a promising role of pharmaceutical cocrystals in bringing novel and improved medicines to the market, which has been further fuelled by the recent guidance from the major regulatory agencies.

Solvent Content Controlling Strategy for Cocrystallizable Polyesters Enables a Stress-Free Two-Way Shape Memory Effect with Wider Service Temperatures.

It is challenging to enhance the stress-free two-way shape memory (stress-free TWSM) effect to obtain a wide range of response temperatures. Herein, a polycaprolactone (PCL)/poly(ω-pentadecalactone) (PPDL) is photocured under UV light irradiation in the solvent of 1,1,2-trichloroethane (TCA), to obtain a series of cross-linked polyesters (CPES). Controlling solvent content (SC) which is removed after the polymerization allows the yielded CPES to perform a regulatable thermodynamic and stress-free TWSM properties. High SC is beneficial to reduce the degree of chain overlap (C/C* ) of PPDL chain segments in the PCL-based CPES network, then causes the cocrystallization of PCL and PPDL and yielding an additional melting-transitions (Tm ). An enhanced stress-free TWSM is obtained in high SC samples (CPES-15-90), reflected in the attainment of a wide range of response temperature, which means a wider service temperature. The enhancement is reflected in higher reversible strain of high SC samples compared with the samples prepared with low SC when varying high trigger temperature (Thigh ). Even at high Thigh , the high SC sample still has reversible strain. Therefore, controlling SC strategy for photocuring copolyester not only provides a new preparation approach for high-performance shape memory (SM) polymers, but also offers new condensed polymer structure to explore.

Induced crystallization for the simultaneous removal of hardness-iron-manganese in groundwater: An experimental study.

Hardness, iron, and manganese are common groundwater pollutants, that frequently surpass the established discharge standard concentrations. They can be effectively removed, however, through induced crystallization. This study has investigated the effectiveness of the simultaneous removal of hardness-iron-manganese and the crystallization kinetics of calcium carbonate during co-crystallization using an automatic potentiometric titrator. The impacts pH, dissolved oxygen (DO), and ion concentration on the removal efficiency of iron and manganese and their influence on calcium carbonate induced crystallization were assessed. The results suggest that pH exerts the most significant influence during the removal of hardness, iron, and manganese, followed by DO, and then the concentration of iron and manganese ions. The rate of calcium carbonate crystallization increased with pH, stabilizing at a maximum of 10-10 m/s. Iron and manganese can be reduced from an initial level of 4 mg/L to <0.3 mg/L and 0.1 mg/L, respectively. The removal rate of iron, however, was notably higher than that of manganese. The DO concentration correlates positively with the removal of iron and manganese but has minimal impact on the calcium carbonate crystallization process. During the removal of iron and manganese, competitive interactions occur with the substrate, as increases in the concentration of one ion will inhibit the removal rate of the other. Characterization of post-reaction particles and mechanistic analysis reveals that calcium is removed through the crystallization of CaCO3, while most iron is removed through precipitation as Fe2O3 and FeOOH. Manganese is removed via two mechanisms, crystallization of manganese oxide (MnO2/Mn2O3) and precipitation. Overall, this research studies the removal efficiency of coexisting ions, the crystallization rate of calcium carbonate, and the mechanism of simultaneous removal, and provides valuable data to aid in the development of new removal techniques for coexisting ions.

Host-Guest Cocrystallization of Phenanthrene[2]arene Macrocycles Facilitating Structure Determination of Liquid Organic Molecules.

Single-crystal X-ray diffraction analysis has emerged as the most reliable method for determining the structures of organic molecules. However, numerous analytes, such as liquid organic molecules, pose challenges in crystallization, making their structures directly elusive via X-ray crystallography methods. Herein, we introduced the rapid cocrystallization of a macrocycle named phenanthrene[2]arene (PTA, host) with 15 liquid organic molecules (guests). The guest liquid organic molecules were successively cocrystallized with the aid of the PTA host. Moreover, the chemical structures of the liquid organic molecules could be determined through single-crystal X-ray diffraction analysis. PTA exhibited high adaptivity and was capable of encapsulating liquid organic molecules without forming covalent bonds or strong directional interactions. The results revealed that the adaptive crystals of PTA exhibited excellent cocrystallization capacity. Weak noncovalent interactions between the host and guest molecules were crucial for organizing the guests in an ordered pattern.

Co-crystallization of Hesperidin with different co-formers to enhance solubility, antioxidant and anti-inflammatory activities.

Hesperidin (HSP) is a natural flavonoid glycoside with very low aqueous solubility and a slow dissolution rate, limiting its effectiveness. This study aims to address these issues by creating co-crystals of hesperidin with water-soluble small molecules (co-formers) such as L-arginine, glutathione, glycine, and nicotinamide. Using the solvent drop grinding method, we prepared three different molar ratios of hesperidin to co-formers (1:1, 1:3, and 1:5) and conducted in-vitro solubility and dissolution studies. The results demonstrated that the prepared co-crystals exhibited significantly enhanced solubility and dissolution rates compared to untreated hesperidin. Of particular note, the HSP co-crystals formula (HSP: L-arg 1:5) displayed approximately 4.5 times higher dissolution than pure hesperidin. Further analysis using FTIR, powder x-ray diffraction patterns, and DSC thermograms validated the formation of co-crystals between HSP and L-arginine. Additionally, co-crystallization with L-arginine improved the in vitro anti-inflammatory and antioxidant activities of hesperidin compared to the untreated drug. This study highlights the potential of using water-soluble small molecules (co-formers) through co-crystallization to enhance the solubility, dissolution, and biological activities of poorly water-soluble drugs. Furthermore, in vivo studies are crucial to validate these promising results.

Boosting Stimulated Emission via a Hydrogen-Bonded Co-Crystallization Approach in Molecular Crystals.

Stimulated emission of organic π-conjugated molecule in solid state remains a significant challenge, mainly involving the mode of molecular stacking that invariably alters the photo-physical processes. Herein, we successfully realized the stimulated emission in molecular crystals using a hydrogen-bonded co-crystallization strategy. Two hydrogen-bonded co-crystals, obtained from 1,4-bis-p-cyanostyrylbenzene (CNDSB) and two types of co-formers, can boost stimulated emission and show decent amplified spontaneous emission (ASE), whereas the parent CNDSB crystal is not SE-active. Crystal structural analysis demonstrated that the co-crystallization eliminated excimer formation. The resulting higher kr and shorter excited-lifetime led to a larger stimulated-emission cross section, which benefited to the occurrence of ASE. Simultaneously, the uniaxial arrangements along long axis of co-crystal together contributed to highly polarized emission. This system presents very rare evidence of boosting stimulated emission by binary co-crystallization, which enriches our insights into organic solid-state lasers.

Biological and Structural Analyses of New Potent Allosteric Inhibitors of HIV-1 Integrase.

HIV-1 integrase-LEDGF allosteric inhibitors (INLAIs) share the binding site on the viral protein with the host factor LEDGF/p75. These small molecules act as molecular glues promoting hyper-multimerization of HIV-1 IN protein to severely perturb maturation of viral particles. Herein, we describe a new series of INLAIs based on a benzene scaffold that display antiviral activity in the single digit nanomolar range. Akin to other compounds of this class, the INLAIs predominantly inhibit the late stages of HIV-1 replication. A series of high-resolution crystal structures revealed how these small molecules engage the catalytic core and the C-terminal domains of HIV-1 IN. No antagonism was observed between our lead INLAI compound BDM-2 and a panel of 16 clinical antiretrovirals. Moreover, we show that compounds retained high antiviral activity against HIV-1 variants resistant to IN strand transfer inhibitors and other classes of antiretroviral drugs. The virologic profile of BDM-2 and the recently completed single ascending dose phase I trial (ClinicalTrials.gov identifier: NCT03634085) warrant further clinical investigation for use in combination with other antiretroviral drugs. Moreover, our results suggest routes for further improvement of this emerging drug class.

A structure and knowledge-based combinatorial approach to engineering universal scFv antibodies against influenza M2 protein.

BACKGROUND: The influenza virus enters the host via hemagglutinin protein binding to cell surface sialic acid. Receptor-mediated endocytosis is followed by viral nucleocapsid uncoating for replication aided by the transmembrane viral M2 proton ion channel. M2 ectodomain (M2e) is a potential universal candidate for monoclonal antibody therapy owing to its conserved nature across influenza virus subtypes and its importance in viral propagation. METHODS: The phage-displayed naive human antibody libraries were screened against the short stretch of the N-terminal 10-mer peptide (SLLTEVETPI) of the M2e. ELISA, BLI, and flow cytometry assays were used to examine scFv binding to M2e epitopes. The scFv crystal structures were determined to examine the nature of the interactions. The potencies of the scFvs against the influenza virus were demonstrated by real-time PCR and confocal microscopy imaging. RESULTS: The four unique scFv clones were obtained from the scFv phage-display antibody libraries and shown to exhibit binding with the 10-mer conserved part of the M2e and with full-length M2 protein expressed on the HEK293T cells. The crystal structure of scFv AU1 with M2e peptide showed the peptide as a dimer in the parallel beta-sheet conformation bound at the interface of two scFv CDRs. The scFv AU1 significantly restricted the release of H1N1 virus progeny from the infected A549 cells. CONCLUSION: This structural and biochemical study showcased the binding of antibody scFv molecules with M2e peptide dimer, providing the structural insights for the function effect in terms of recognizing and restricting the release of new viral particles from an infected host cell.

Modulating Pharmaceutical Properties of Berberine Chloride through Cocrystallization with Benzendiol Isomers.

PURPOSE: To synthesize and characterize new cocrystals of berberine chloride (BCl) for potential pharmaceutical tablet formulation. METHODS: Solutions of BCl with each of three selected cocrystal formers, catechol (CAT), resorcinol (RES), and hydroquinone (HYQ) were slowly evaporated at room temperature to obtain crystals. Crystal structures were solved using single crystal X-ray diffraction. Bulk powders were characterized by powder X-ray diffraction, thermogravimetric-differential scanning calorimetry, FTIR, dynamic moisture sorption, and dissolution (both intrinsic and powder). RESULTS: Single crystal structures confirmed the formation of cocrystals with all three coformers, which revealed various intermolecular interactions that stabilized crystal lattices, including O-H···Cl- hydrogen bonds. All three cocrystals exhibited better stability against high humidity (up to 95% relative humidity) at 25 ℃ and higher intrinsic and powder dissolution rates than BCl. CONCLUSION: The enhanced pharmaceutical properties of all three cocrystals, as compared to BCl, further contribute to the existing evidence that confirms the beneficial role of cocrystallization in facilitating drug development. These new cocrystals expand the structure landscape of BCl solid forms, which is important for future analysis to establish a reliable relationship between crystal structure and pharmaceutical properties.

Unraveling the Co-Crystallization-Charge Transport Relation in Conjugated Polymer Blends via Meniscus-Assisted Solution-Shearing.

The ability to craft the co-crystallization in conjugated polymer blends represents an important endeavor for the enhancement of charge transport. However, simple and efficient approaches to co-crystallization have yet to be realized. Herein, for the first time, a robust meniscus-assisted solution-shearing (MASS) strategy is reported to achieve co-crystallization in the poly(2,5-bis(3-hexylthiophen-2-yl)thieno[3,2-b]thiophene) (PBTTT-C6) and poly(2,5-bis(3-decylthiophen-2-yl)thieno[3,2-b]thiophene) (PBTTT-C10) blended films, and correlate this co-crystalline structure to the charge transport properties. The as-cast PBTTT-C6/PBTTT-C10 blends exhibit co-crystalline or phase-separated structures influenced by their molecular weights. Interestingly, confined-shearing of the initial phase-separated blended solution to MASS produces the formation of their co-crystallization. The co-crystallization kinetics accompanied by the chain packing change and optical properties are scrutinized. Finally, the resulting organic field-effect transistors (OFETs) signify the cocrystal-facilitated charge transport in the blends. Conceptually, this efficient MASS strategy in rendering the co-crystallization in conjugated polymer blends can be readily extended to other conjugated polymer blends of interest for a variety of device applications.

Oxazolo[5,4-f]quinoxaline-type selective inhibitors of glycogen synthase kinase-3α (GSK-3α): Development and impact on temozolomide treatment of glioblastoma cells.

The 2-(3-pyridyl)oxazolo[5,4-f]quinoxalines CD-07 and FL-291 are ATP-competitive GSK-3 kinase inhibitors. Here, we investigated the impact of FL-291 on neuroblastoma cell viability and showed that treatment at 10 µM (i.e. ∼500 times the IC50 against the GSK-3 isoforms) has no significant effect on the viability of NSC-34 motoneuron-like cells. A study performed on primary neurons (non-cancer cells) led to similar results. The structures co-crystallized with GSK-3ß revealed similar binding modes for FL-291 and CD-07, with their hinge-oriented planar tricyclic system. Both GSK isoforms show the same orientations for the amino acids at the binding pocket except for Phe130 (α) and Phe67 (ß), leading to a larger pocket on the opposite side of the hinge region for the α isoform. Calculations of the thermodynamic properties of the binding pockets highlighted the required features of potential ligands; these should have a hydrophobic core (which could be larger in the case of GSK-3ß) surrounded by polar areas (a little more polar in the case of GSK-3α). A library of 27 analogs of FL-291 and CD-07 was thus designed and synthesized by taking advantage of this hypothesis. While the introduction of substituents at different positions of the pyridine ring, the replacement of the pyridine by other heterocyclic moieties, or the replacement of the quinoxaline ring by a quinoline moiety did not lead to any improvement, the replacement of the N-(thio)morpholino of FL-291/CD-07 by a slightly more polar N-thiazolidino led to a significant result. Indeed, the new inhibitor MH-124 showed clear selectivity for the α isoform, with IC50 values of 17 nM and 239 nM on GSK-3α and GSK-3ß, respectively. Finally, the efficacy of MH-124 was evaluated on two glioblastoma cell lines. Although MH-124 alone did not have a significant impact on cell survival, its addition to temozolomide (TMZ) significantly reduced the TMZ IC50 values on the cells tested. The use of the Bliss model allowed a synergy to be evidenced at certain concentrations.

Mechanochemical Preparation, Solid-State Characterization, and Antimicrobial Performance of Copper and Silver Nitrate Coordination Polymers with L- and DL-Arginine and Histidine.

The antimicrobial activity of the novel coordination polymers obtained by co-crystallizing the amino acids arginine or histidine, as both enantiopure L and racemic DL forms, with the salts Cu(NO3)2 and AgNO3 has been investigated to explore the effect of chirality in the cases of enantiopure and racemic forms. The compounds [Cu·AA·(NO3)2]CPs and [Ag·AA·NO3]CPs (AA = L-Arg, DL-Arg, L-His, DL-His) were prepared by mechanochemical, slurry, and solution methods and characterized by X-ray single-crystal and powder diffraction in the cases of the copper coordination polymers, and by powder diffraction and by solid-state NMR spectroscopy in the cases of the silver compounds. The two pairs of coordination polymers, [Cu·L-Arg·(NO3)2·H2O]CP and [Cu·DL-Arg·(NO3)2·H2O]CP, and [Cu·L-Hys·(NO3)2·H2O]CP and [Cu·DL-His·(NO3)2·H2O]CP, have been shown to be isostructural in spite of the different chirality of the amino acid ligands. A similar structural analogy could be established for the silver complexes on the basis of SSNMR. The activity against the bacterial pathogens Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus was assessed by carrying out disk diffusion assays on lysogeny agar media showing that, while there is no significant effect arising from the use of enantiopure or chiral amino acids, the coordination polymers exert an appreciable antimicrobial activity comparable, when not superior, to that of the metal salts alone.

Extraction and Encapsulation of Phytocompounds of Poniol Fruit via Co-Crystallization: Physicochemical Properties and Characterization.

Poniol (Flacourtia jangomas) has beneficial health effects due to its high polyphenolic and good antioxidant activity content. This study aimed to encapsulate the Poniol fruit ethanolic extract to the sucrose matrix using the co-crystallization process and analyze the physicochemical properties of the co-crystalized product. The physicochemical property characterization of the sucrose co-crystallized with the Poniol extract (CC-PE) and the recrystallized sucrose (RC) samples was carried out through analyzing the total phenolic content (TPC), antioxidant activity, loading capacity, entrapment yield, bulk and traped densities, hygroscopicity, solubilization time, flowability, DSC, XRD, FTIR, and SEM. The result revealed that the CC-PE product had a good entrapment yield (76.38%) and could retain the TPC (29.25 mg GAE/100 g) and antioxidant properties (65.10%) even after the co-crystallization process. Compared to the RC sample, the results also showed that the CC-PE had relatively higher flowability and bulk density, lower hygroscopicity, and solubilization time, which are desirable properties for a powder product. The SEM analysis showed that the CC-PE sample has cavities or pores in the sucrose cubic crystals, which proposed that the entrapment was better. The XRD, DSC, and FTIR analyses also showed no changes in the sucrose crystal structure, thermal properties, and functional group bonding structure, respectively. From the results, we can conclude that co-crystallization increased sucrose's functional properties, and the co-crystallized product can be used as a carrier for phytochemical compounds. The CC-PE product with improved properties can also be utilized to develop nutraceuticals, functional foods, and pharmaceuticals.

Exploring the Co-Crystallization of Kojic Acid with Silver(I), Copper(II), Zinc(II), and Gallium(III) for Potential Antibacterial Applications.

Co-crystallization of kojic acid (HKA) with silver(I), copper(II), zinc(II), or gallium(III) salts yielded three 1D coordination polymers and one 0D complex in which kojic acid was present as a neutral or anionic terminal or bridging ligand. All reactions were conducted mechanochemically via ball milling and manual grinding, or via slurry. All solids were fully characterized via single-crystal and/or powder X-ray diffraction. As kojic acid is a mild antimicrobial compound that is widely used in cosmetics, and the metal cations possess antibacterial properties, their combinations were tested for potential antibacterial applications. The minimal inhibition concentrations (MICs) and minimal biocidal concentrations (MBCs) for all compounds were measured against standard strains of the bacteria P. aeruginosa, S. aureus, and E. coli. All compounds exerted appreciable antimicrobial activity in the order of silver, zinc, copper, and gallium complexes.

Comparative assessment of solubility enhancement of itroconazole by solid dispersion and co-crystallization technique: Investigation of simultaneous effect of media composition on drug dissolution.

Solubility of the drug is an important property of the drug as it affects the release, absorption, dissolution rate and ultimately bioavailability of the drug. Hence, the poorly aqueous soluble drug, need to be processed, to enhance its solubility and dissolution. The Biopharmaceutical System of Classification (BCS) II drugs are poorly soluble and have high permeability. Though their good ability to permeate through the membrane make them clinically useful but the problem associated with the solubility restrict their clinical use. Therefore, there is need to improve the solubility of such drug molecules to get effective pharmacological action. Itraconazole (ITZ) is an antifungal agent used in the treatment of fungal infections having poor aqueous solubility as belonging to BCS class II. The present study was aim to enhance the solubility of ITZ by solid dispersion and co-crystallization techniques. Investigation of simultaneous effect of media composition on drug dissolution was also the objective of this work. The ITZ-SD and ITZ-CCs were prepared from ITZ and other excipients like PEG 4000, oxalic acid, fumaric and malic acid by solvent evaporation, kneading technique, slurry conversion and solvent drop grinding methods. The prepared ITZ-SD, ITZ-OA-CCs, ITZ-FA-CCs and ITZ-MA-CCs were evaluated for FTIR, DSC, PXRD, % yield, micromeritic properties. The optimized ITZ-SD and ITZ-CCs were used to compress a tablet and subject to post-compression parameters. The results of FTIR and DSC showed the absence of interaction between the drug and excipients. The PXRD pattern demonstrated the formation of crystalline structures with 6 folds increased in solubility during saturation solubility analysis. In vitro dissolution was carried out in dissolution media with different pH which shows the maximum release from ITZ-SD and ITZ-CCs in pH 6.8. This also revealed the highly pH dependent solubility and dissolution behavior of the weakly basic BCS class II drug (ITZ) with pKa value of 3.7. The overall results in this study indicated the potential of solid dispersion and co-crystals for enhancement of solubility of the poorly water-soluble drugs.

Fully Bridged Triphenylamines Comprising Five- and Seven-Membered Rings.

A family of fully bridged triphenylamines with embedded 5- and 7-membered rings is presented. The compounds are potent electron donors capable to undergo donor/acceptor interactions with strong cyano-based acceptors both in the solid state and solution. These interactions were evaluated by IR and UV/vis spectroscopy as well as X-ray crystallography. The vinylene-bridged compound was oxidized to the corresponding 1,2-diketone which readily underwent acid-catalyzed condensation with selected 1,2-phenylenediamines. The resulting π-extended quinoxaline derivatives represent valuable building blocks for the development of functional chromophores upon appropriate functionalization.

Recent advances in the field of chiral crystallization.

Crystallization is one of the largest and most economical bulk purification techniques used in industry today. There has been an increase in demand for enantiomerically pure compound production for research, organic synthesis, pharmaceutical drug production, and other applications. Even after asymmetric synthesis, chiral purification will always be necessary. The focus of this review is on recent advances in chiral crystallization for the purification of enantiomers. A comprehensive discussion of three techniques and their mechanisms is provided, namely: attrition-enhanced deracemization, cocrystallization, and inorganic ionic cocrystallization. Several examples of attrition-enhanced deracemization are discussed. The key advantage of this technique is that it eliminates enantiomeric waste and can be used to produce enantiomeric excesses of greater than 99% from racemic mixtures. Chiral cocrystallization is examined, with over 60 cocrystallizing compounds, as an excellent means for enantiomeric enrichment. Selective chiral inclusion complexation was shown to be a novel approach for the formation of cocrystals. Chiral inorganic ionic cocrystallization is a new technique involving the formation of cocrystals between chiral ligands and certain metal salts in order to produce conglomerate crystal behavior in otherwise racemic compounds.