Lipase as a Chiral Selector Immobilised on Carboxylated Single-Walled Carbon Nanotubes and Encapsulated in the Organic Polymer Monolithic Capillary for Nano-High Performance Liquid Chromatography Enantioseparation of Racemic Pharmaceuticals.

Herein, we report the preparation of lipase immobilised on single-walled carbon nanotubes (SWCNTs) as an enantioselector for capillary monolithic columns and their application in the chiral separation of racemic pharmaceuticals. The columns were prepared through the encapsulation of functionalised SWCNTs (c-SWCNTs) within an organic monolithic polymer, followed by the immobilisation of lipase over the obtained monolith, over a three-day (L1) and five-day (L2) period. The prepared columns were tested for the enantioselective nano-HPLC separation of 50 racemic drugs. A suitable resolution was achieved for 25 drugs using nano-RP-HPLC conditions for both the L1 and L2 capillaries, while no specific resolution was detected under normal-phase HPLC conditions. The developed c-SWCNT-lipase-based polymeric monolithic capillaries are a promising expansion for separating pharmaceutical enantiomers' using nano-HPLC.

Daptomycin: A Novel Macrocyclic Antibiotic as a Chiral Selector in an Organic Polymer Monolithic Capillary for the Enantioselective Analysis of a Set of Pharmaceuticals.

Daptomycin, a macrocyclic antibiotic, is here used as a new chiral selector in preparation of chiral stationary phase (CSP) in a recently prepared polymer monolithic capillary. The latter is prepared using the copolymerization of the monomers glycidyl methacrylate (GMA) and ethylene glycol dimethacrylate (EGDMA) in the presence of daptomycin in water. Under reversed phase conditions (RP), the prepared capillaries were tested for the enantioselective nanoliquid chromatographic separation of fifty of the racemic drugs of different pharmacological groups, such as adrenergic blockers, H1-blockers, NSAIDs, antifungal drugs, and others. Baseline separation was attained for many drugs under RP-HPLC. Daptomycin expands the horizon of chiral selectors in HPLC.

An insight into chiral monolithic stationary phases for enantioselective high-performance liquid chromatography applications.

In this review, three main classes of chiral monolithic stationary phases, namely silica-, organic polymer-, and hybrid-based monolithic stationary phases, are covered. Their preparations, applications, and advantages compared with the conventional-packed and open-tubular capillary columns are discussed. A detailed description of the different types and techniques used for the introduction of chiral selectors into the monolithic matrices such as immobilization, functionalization, coating, encapsulation, and bonding. Special emphasis is given to the recent developments of chiral selectors in HPLC monolithic stationary phases during the past 18 years.

On the Enantioselective HPLC Separation Ability of Sub-2 µm Columns: Chiralpak® IG-U and ID-U.

Silica with a particle size of 3-5 µm has been widely used as selector backbone material in 10-25 cm HPLC chiral columns. Yet, with the availability of 1.6 µm particles, shorter, high-efficiency columns practical for minute chiral separations are possible to fabricate. Herein, we investigate the use of two recently commercialized sub-2 µm columns with different substituents. Thus, Chiralpak® IG-U and ID-U were used in HPLC for the fast enantioseparation of a set of drugs. Chiralpak® IG-U [amylose tris (3-chloro-5-methylphenylcarbamate)] has two substituents on the phenyl ring, namely, a withdrawing chlorine group in the third position and a donating group in the fifth position. Chiralpak® ID-U [amylose tris (3-chlorophenylcarbamate)] has only one substituent on the phenyl ring, namely a withdrawing chlorine group. Their applications in three liquid chromatography modes, namely, normal phase, polar organic mode, and reversed phase, were demonstrated. Both columns have similar column parameters (50 mm length, 3 mm internal diameter, and 1.6 µm particle size) with the chiral stationary phase as the only variable. Improved chromatographic enantioresolution was obtained with Chiralpak® ID-U. Amino acids partially separated were reported for the first time under an amylose-based sub-2-micron column.

Colistin Sulfate Chiral Stationary Phase for the Enantioselective Separation of Pharmaceuticals Using Organic Polymer Monolithic Capillary Chromatography.

A new functionalized polymer monolithic capillary with a macrocyclic antibiotic, namely colistin sulfate, as chiral selector was prepared via the copolymerization of binary monomer mixtures consisting of glycidyl methacrylate (GMA) and ethylene glycol dimethacrylate (EGDMA) in porogenic solvents namely 1-propanol and 1,4-butanediol, in the presence of azobisiso-butyronitrile (AIBN) as initiator and colistin sulfate. The prepared capillaries were investigated for the enantioselective nano-LC separation of a group of racemic pharmaceuticals, namely, α- and ß-blockers, anti-inflammatory drugs, antifungal drugs, norepinephrine-dopamine reuptake inhibitors, catecholamines, sedative hypnotics, antihistaminics, anticancer drugs, and antiarrhythmic drugs. Acceptable separation was achieved for many drugs using reversed phase chromatographic conditions with no separation achieved under normal phase conditions. Colistin sulfate appears to be useful addition to the available macrocyclic antibiotic chiral phases used in liquid chromatography.

Design and Synthesis of Novel Chiral Dirhodium(II) Carboxylate Complexes for Asymmetric Cyclopropanation Reactions.

A novel approach to the design of dirhodium(II) tetracarboxylates derived from (S)-amino acid ligands is reported. The approach is founded on tailoring the steric influences of the overall catalyst structure by reducing the local symmetry of the ligand's N-heterocyclic tether. The application of the new approach has led to the uncovering of [Rh2 (S-tert PTTL)4 ] as a new member of the dirhodium(II) family with extraordinary selectivity in cyclopropanation reactions. The stereoselectivity of [Rh2 (S-tert PTTL)4 ] was found to be comparable to that of [Rh2 (S-PTAD)4 ] (up to >99 % ee), with the extra benefit of being more synthetically accessible. Correlations based on X-ray structures to justify the observed enantioinduction are also discussed.

Cyclodextrin-Functionalized Monolithic Capillary Columns: Preparation and Chiral Applications.

In this review, the recently reported approaches for the preparation of cyclodextrin-functionalized capillary monolithic columns are highlighted, with few applications in chiral separations using capillary liquid chromatography (CLC) and capillary electrochromatography (CEC). Chirality 28:97-109, 2016. © 2015 Wiley Periodicals, Inc.

Enantioselective nano liquid chromatographic separation of racemic pharmaceuticals: a facile one-pot in situ preparation of lipase-based polymer monoliths in capillary format.

New affinity monolithic capillary columns of 150 µm internal diameter were prepared in situ fused glass capillary via either immobilization or encapsulation of Candida antarctica lipase B (CALB) on or within polymer monoliths, respectively. The immobilized lipase-based monoliths were prepared via copolymerization of 19.1% monomers (8.9% MMA and 10.2% GMA), 19.8% EDMA, and 61.1% porogens (54.2% formamide and 6.9% 1-propanol) w/w or 20% GMA, 20% EDMA, and 60% porogens (51.6% cyclohexanol and 8.4% 1-dodecanol) in the presence of AIBN (1%) as a radical initiator. This was followed by pumping a solution of lipase through the capillaries and rinsing with potassium phosphate buffer. On the other hand, the encapsulated lipase-based monoliths were prepared via copolymerization of 20% monomers (GMA), 20% EDMA, and 60% porogens (48% 1-propanol, 6% 1,4-butanediol) or 16.4% monomers (16% BuMA, 0.4% SPMA), 23.6% EDMA, and 60% porogens (36% 1-propanol, 18% 1,4-butanediol along with 6% lipase aqueous solution in potassium phosphate buffer. The prepared capillary columns were investigated for the enantioselective nano liquid chromatographic separation of a set of different classes of racemic pharmaceuticals, namely, α- and ß-blockers, antiinflammatory drugs, antifungal drugs, dopamine antagonists, norepinephrine-dopamine reuptake inhibitors, catecholamines, sedative hypnotics, diuretics, antihistaminics, anticancer drugs, and antiarrhythmic drugs. Run-to-run repeatability was quite satisfactory. The encapsulated lipase-based capillary monolith showed better enantioselective separations of most of the investigated compounds. Baseline separation was achieved for alprenolol, atenolol, bromoglutithimide, carbuterol, chloropheneramine, cizolertine carbinol, 4-hydroxy-3-methoxymandelic acid, desmethylcizolertine, nomifensine, normetanephrine, and sulconazole under reversed phase chromatographic conditions. A speculation about the understanding of the chiral recognition mechanism of lipase-based monoliths toward the investigated pharmaceuticals is discussed.

Conventional Chiralpak ID vs. capillary Chiralpak ID-3 amylose tris-(3-chlorophenylcarbamate)-based chiral stationary phase columns for the enantioselective HPLC separation of pharmaceutical racemates.

A comparative enantioselective analysis using immobilized amylose tris-(3-chlorophenylcarbamate) as chiral stationary phase in conventional high-performance liquid chromatography (HPLC) with Chiralpak ID (4.6 mm ID × 250 mm, 5 µm silica gel) and micro-HPLC with Chiralpak ID-3 (0.30 mm ID × 150 mm, 3 µm silica gel) was conducted. Pharmaceutical racemates of 12 pharmacological classes, namely, α- and ß-blockers, anti-inflammatory drugs, antifungal drugs, dopamine antagonists, norepinephrine-dopamine reuptake inhibitors, catecholamines, sedative hypnotics, diuretics, antihistaminics, anticancer drugs, and antiarrhythmic drugs were screened under normal phase conditions. The effect of an organic modifier on the analyte retentions and enantiomer recognition was investigated. Baseline separation was achieved for 1-acenaphthenol, carprofen, celiprolol, cizolirtine carbinol, miconazole, tebuconazole, 4-hydroxy-3-methoxymandelic acid, 1-indanol, 1-(2-chlorophenyl)ethanol, 1-phenyl-2-propanol, flavanone, 6-hydroxyflavanone, 4-bromogluthethimide, and pentobarbital on the 4.6 mm ID packed with a 5 µm silica column using conventional HPLC. Nonetheless, baseline separation was achieved for aminoglutethimide, naftopidil, and thalidomide on the 0.3 mm ID packed with a 3 µm silica capillary column.

Chiral dirhodium(II) carboxylates and carboxamidates as effective chemzymes in asymmetric synthesis of three-membered carbocycles.

In this review the recent advances in the utilization of two of the most important classes of dirhodium(II) paddlewheel complexes, dirhodium(II) carboxylates and carboxamidates, as chemzymes in inter- and intramolecular asymmetric cyclopropanation, as well as cyclopropenation reactions are discussed.

Cucurbituril: chiral applications.

This review brings together the past and current methods for synthesizing the classical cucurbit[n]uril (Q[n]), structural variants, and derivatives. Here we refer to the first family of Q[n] as " classical," where the cavity is spheroidal and carry no substituents at any of the equatorial methine carbons or the methylene bridging carbons. The synthetic background and general physical and chemical properties of the Q[n] as molecular hosts is discussed. Particular attention is drawn to the synthesis of structural variants that have significance for chiral recognition properties such as (±)-bis-nor-seco-Q[6] and (±)-bis-nor-seco-Q[10]. Furthermore, examples of chiral recognition, enantio- and stereoselectivity using the achiral Q[n] as supramolecular structures with a chiral function directly or indirectly via another chiral agent are also discussed.

Rh2 (S-1,2-NTTL)4 : A novel Rh2 (S-PTTL)4 analog with lower ligand symmetry for asymmetric synthesis of chiral cyclopropylphosphonates.

A new series of dirhodium(II) tetracarboxylate was derived from N-1,2-naphthaloyl-(S)-amino acid ligands. In terms of enantioselectivity, Rh2 (S-1,2-NTTL)4 () derived from N-1,2-naphthaloyl-(S)-tert-leucine, was the best-performing catalyst among the new series in the enantioselective synthesis of cyclopropylphosphonate derivatives (up to >99% enantiomeric excess). A predictive model was proposed to justify the observed high enantiomeric induction exhibited by Rh2 (S-1,2-NTTL)4 with donor-acceptor phosphonate carbenoids.

Organic/hybrid nanoparticles and single-walled carbon nanotubes: preparation methods and chiral applications.

Nanoparticles are molecular-sized solids with at least one dimension measuring between 1-100 nm or 10-1000 nm depending on the individual discipline's perspective. They are aggregates of anywhere from a few hundreds to tens of thousands of atoms which render them larger than molecules but smaller than bulk solids. Consequently, they frequently exhibit physical and chemical properties somewhere between. On the other hand, nanocrystals are a special class of nanoparticles which have started gaining attention recently owing to their unique crystalline structures which provide a larger surface area and promising applications including chiral separations. Hybrid nanoparticles are supported by the growing interest of chemists, physicists, and biologists, who are researching to fully exploit them. These materials can be defined as molecular or nano-composites with mixed (organic or bio) and inorganic components, where at least one of the component domain has a dimension ranging from a few Å to several nanometers. Similarly, and due to their extraordinary physical, chemical, and electrical properties, single-walled carbon nanotubes have been the subject of intense research. In this short review, the focus is mainly on the current well-established simple preparation techniques of chiral organic and hybrid nanoparticles as well as single-walled carbon nanotubes and their applications in separation science. Of particular interest, cinchonidine, chitosan, and ß-CD-modified gold nanoparticles (GNPs) are discussed as model examples for organic and hybrid nanoparticles. Likewise, the chemical vapor deposition method, used in the preparation of single-walled carbon nanotubes, is discussed. The enantioseparation applications of these model nanomaterials is also presented.

An insight to chiral monolith for enantioselective nano and micro HPLC: preparation and applications.

This review gives an overview of chiral separation principles and their application in enantioselective nano/micro high performance liquid chromatography (n/µ-HPLC) using chiral monolith. In particular, developments in silica and polymer chiral monolithic stationary phases are presented. The preparation and applications of chiral monoliths, the basic chiral separation principles and the mechanisms are discussed.

A Polymer-based Monolithic Capillary Column with Polymyxin-B Chiral Selector for the Enantioselective Nano-High Performance Liquid Chromatographic Pharmaceutical Analysis.

Herein, we report the first use of Polymyxin-B antibiotic as a enantio-selector in polymer monolithic capillary. The capillaries were functionalised, characterized and tested for the enantioselective nano-HPLC separation of 50 racemic pharmaceutical drugs. They have been easily prepared by immobilizing Polymyxin-B over the organic polymer for 48 h (P1) or encapsulating Polymyxin-B within the organic polymer (P2) and tested for the enantioselective resolution of racemic drugs. Acceptable resolution was achieved for 21 drugs using RP-HPLC conditions on both (P1) and (P2) capillary columns, while no separation was observed under NP-HPLC conditions. Polymyxin-B is commercially available, easily solubilized and stable in both acidic and neutral media. The developed Polymyxin-B-based polymer monolithic capillaries provide a promising expansion of platform in enantioselective HPLC separations.

Optimizing dirhodium(II) tetrakiscarboxylates as chiral NMR auxiliaries.

Thirteen enantiopure paddlewheel-shaped dirhodium(II) tetrakiscarboxylate complexes have been checked for their efficiency in the dirhodium method (differentiation of enantiomers by NMR spectroscopy); six of them are new. Their diastereomeric dispersion effects were studied and compared via so-called key numbers KN. Adducts of each complex were tested with five different test ligands representing all relevant donor properties from strong (phosphane) to very weak (ether). Only one of them, the dirhodium complex with four axial (S)-N-2,3-naphthalenedicarboxyl-tert-leucinate groups (N23tL), showed results significantly better for all ligands than the conventional complex Rh* [Rh(II)(2)[(R)-(+)-MTPA](4); MTPA = methoxytrifluoromethylphenylacetate]. On the basis of (1)H{(1)H} NOE spectroscopy and X-ray diffraction, a combination of favourable anisotropic group orientation and conformational flexibility is held responsible for the high efficiency of N23tL in enantiodifferentiation. Both complexes, Rh* and N23tL, are recommended as chiral auxiliaries for the dirhodium experiment.

New silica monolith bonded chiral (R)-γ butyrolactone for enantioselective micro high-performance liquid chromatography.

A single low-molecular mass chiral selector namely (R)-acryloyloxy-ß-ß-dimethyl-γ-butyrolactone has been bonded to a modified silica-based monolith to form a new brush-type chiral stationary phase for micro-high performance liquid chromatography (HPLC) separation.

Recent advances in silica-based monoliths: preparations, characterizations and applications.

This mini-review describes recent progress (2009-2010) in the field of silica-based monolith with special emphasis on the preparation, characterization and applications.

Evaluating efficacy of intravenous carbetocin in reducing blood loss during abdominal myomectomy: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of carbetocin versus placebo in decreasing intraoperative blood loss and the need for blood transfusion during abdominal myomectomy. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Tertiary university hospital from September 2019 to February 2020. PATIENT(S): A total of 138 women with symptomatic leiomyoma who were candidates for abdominal myomectomy (n = 69 in each group). INTERVENTION(S): We randomized the study participants in a 1:1 ratio to carbetocin and placebo groups. Intravenous 100 µg carbetocin or placebo was administered slowly after induction of anesthesia. MAIN OUTCOME MEASURE(S): Intraoperative blood loss, need for blood transfusion, postoperative hemoglobin, operative time, length of hospitalization, and drug side-effects. RESULT(S): The baseline characteristics were similar among all groups. Carbetocin had significantly lower intraoperative blood loss compared with placebo (mean difference 184 mL). Hemoglobin level 24 hours after surgery was significantly lower in the placebo group than in the carbetocin group (9.1 ± 0.8 vs. 10.3 ± 0.6 g/dL). Eight women in the carbetocin group needed blood transfusion compared with 17 in placebo group. Operative time, length of hospitalization, and side-effects were similar in both groups. CONCLUSION(S): A single preoperative intravenous dose of 100 µg carbetocin is a simple, practical, and effective method of decreasing intraoperative blood loss and the need for blood transfusion during abdominal myomectomy, with tolerable, few, nonsignificant side-effects. CLINICAL TRIAL REGISTRATION NUMBER: NCT04083625.

Direct enantioselective HPLC monitoring of lipase-catalyzed kinetic resolution of flurbiprofen.

The solvent versatility of Chiralpak IB, a 3,5-dimethylphenylcarbamate derivative of cellulose-based chiral stationary phase, is demonstrated in the direct enantioselective HPLC monitoring of lipase-catalyzed kinetic resolution of flurbiprofen in nonstandard HPLC organic solvents. Nonstandard HPLC organic solvents were used as the reaction media for the lipase-catalysis and in mean time as diluent to dissolve the "difficult to dissolve" enzyme substrate (the acid) and as eluent for the simultaneous enantioselective HPLC baseline separation of both substrate and product in one run without any further derivatization.