Nanoemulsions as Versatile Formulations for Paclitaxel Delivery: Peroral and Dermal Delivery Studies in Rats

Pathogenesis of psoriasis involves the keratinocytes in epidermis as well as the angiogenesis involving deeper skin layers. So, the drug delivery strategy should be customized to localize paclitaxel (PCL) inside both layers. In this investigation, in order to achieve penetration of PCL into deeper skin layers while minimizing the systemic escape, a nanoemulsion (NE) was formulated and evaluated its in vivo pharmacokinetic performance. Further, the same formulation was explored for peroral bioavailability enhancement of PCL. Upon dermal application, the drug was predominantly localized in deeper skin layers, with minimal systemic escape. When orally administered as NE, PCL was rapidly absorbed reaching a steady-state value of 3.5μg/ml in 30minutes, and steady-state levels persisted up to 18hours. This has amounted to an absolute bioavailability of 70.62%. Inhibition of P-glycoprotein efflux by d-α-tocopheryl polyethyleneglycol 1,000 succinate and labrasol would have contributed to the enhanced peroral bioavailability of PCL. This investigation provides direct evidence on the localization of large molecular weight, lipophilic drug, PCL, in dermis. Further, the NE formulation has enhanced the peroral bioavailability significantly to more than 70%. The developed NE formulation was safe and effective for both peroral and dermal delivery of PCL

GR-384 Benchmarking Network Service Performance Using the POWDER Wireless Testbed

5G RAN slicing provides a way to split network infrastructure into self-contained slices which can have various virtual network functions (VNFs) mapped onto them. Much work has gone into creating robust mapping and resource allocation algorithms in order to efficiently embed VNFs onto the available nodes in a slice. However, in order to most efficiently embed these VNFs we need to understand the resource and bandwidth needs of the services we are trying to embed. This project seeks to provide an accurate assessment of the needs of three commonly used network services. We do this by testing each network service using real world physical machines on the POWDER network testbed. We collect bandwidth and CPU usage data from each test and use it to analyze the needs of the network service when being embedded onto physical nodes during network slicing

Novel co-crystals of the nutraceutical sinapic acid

Sinapic acid (SA) is a nutraceutical with known anti-oxidant, anti-microbial, anti-inflammatory, anti-cancer, and anti-anxiety properties. Novel co-crystals of SA were prepared with co-formers belonging to the category of GRAS [isonicotinic acid (INC), nicotinamide (NIA)], non-GRAS [4-pyridinecarbonitrile (PYC)], and active pharmaceutical ingredients (APIs) [6-propyl-2-thiouracil (PTU)] list of compounds. Structural study based on the X-ray crystal structures revealed the intermolecular hydrogen-bonded interactions and molecular packing. The crystal structure of sinapic acid shows the anticipated acid-acid homodimer along with discrete hydrogen bonds between the acid carbonyl and the phenolic moiety. The robust acid-acid homodimer appears to be very stable and is retained in the structures of two co-crystals (SA[middle dot]NIA and SA[middle dot]PYC). In these cases, co-crystallization occurs via intermolecular phenol O-H[three dots, centered]Naromatic hydrogen bonds between the co-formers. In the SA[middle dot]PTU[middle dot]2MeCN co-crystal the acid-acid homodimer gives way to the anticipated acid-amide heterodimer, with the phenolic moiety of SA hydrogen-bonded to acetonitrile. Attempts at obtaining the desolvated co-crystal led to lattice breakdown, thus highlighting the importance of acetonitrile in the formation of the co-crystal. Among the co-crystals examined, SA[middle dot]INC (5 weeks), SA[middle dot]NIA (8 weeks) and SA[middle dot]PYC (5 weeks) were found to be stable under accelerated humidity conditions (40 [degree]C, 75% RH), whereas SA[middle dot]PTU[middle dot]2MeCN decomposed after one week into individual components due to solvent loss

Exploring the crystal landscape of 3-methyl-2-phenylbutyramide: crystallization of metastable racemic forms from the stable conglomerate

In the solid state (±)-3-methyl-2-phenylbutyramide 1 spontaneously resolves into a conglomerate (Form I) that crystallizes in a racemic form (Form II) upon evaporation from the melt, a rarely reported phenomenon. An additional racemic polymorph, Form III, has been characterized, and the thermodynamic relationship between the three forms established by a variety of computational and experimental methods including grinding, slurry crystallization and seeding techniques. Both racemic Forms II and III are metastable and readily convert to the more stable conglomerate, Form I. Density Functional Theory calculations of the different polymorphs of 1 show that the enantiomers of 1 (R & S) are more stable than both racemic forms

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

Efficient S-acylation of thiourea

Efficient S-acylation of thiourea using a variety of acid chlorides is reported. Structurally diverse aryl and alkyl substrates are compatible with this methodology. Confirmation that acylation occurs exclusively­ on the sulfur atom of thiourea is provided by single-crystal X-ray crystallographic analysis

Regioselective thermal [3+2]-dipolar cycloadditions of α-diazoacetates with α-sulfenyl/sulfinyl/sulfonyl-β-chloroacrylamide derivatives to form densely functionalised pyrazoles

Highly regioselective synthetic methodology leading to densely functionalised C(3), C(4) and C(5) substituted pyrazoles 10a–q, 14a‐i and 16a–g via thermal [3+2]‐dipolar cycloaddition, of α‐diazoacetates and α‐thio‐β‐chloroacrylamides, at the sulfide, sulfoxide and sulfone levels of oxidation, is described. This method allows access to C(4)‐sulfenyl or sulfonyl pyrazoles, through migration of the sulfur substituent at the sulfide and sulfone oxidation levels, while elimination of the sulfinyl group leading to 3,5‐disubstituted pyrazoles, is observed. While the sulfide migration is readily rationalised, the carbon to carbon 1,2‐sulfonyl migration is unprecedented and mechanistically intriguing. The synthetically versatile generation of densely functionalised pyrazoles containing substituents amenable to further modification offers advantages over alternative synthetic routes. Isolation of the N‐alkylated pyrazoles 11a and 12a as by‐products from the cycloaddition through further reaction of the pyrazoles 10 with excess α‐diazoacetate, proved useful in rationalising the tautomeric behaviour evident in the NMR spectra of the pyrazoles, with the position of tautomeric equilibrium influenced by solvent and substituents

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

Epimers with distinct mechanical behaviours

This study highlights the impact of relative stereochemistry in epimer compounds on their mechanical properties; the crystals of one series of esters are ductile and deform plastically upon bending, whereas the other series are all brittle. Nanoindentation studies show that the hardness, H, and elastic moduli, E, of the brittle crystals are substantially larger than those of the ductile ones. For the brittle crystals, the H values range from 153(10) to 293(37) MPa and E from 2.85(0.33) to 9.10(0.51) GPa, whereas for the ductile crystals, the H values range from 76(2) to 125(11) MPa and E from 1.40(0.36) and 2.75(0.06) GPa. These are rationalized by recourse to the distinct crystal structural features, especially in terms of interdigitation in the molecular planes in the brittle crystals and slip planes in the ductile crystals. The indentation fracture toughness, Kc, values of the (2′S) crystals are higher than those typically reported for molecular crystals, due to the corrugated nature of their crystal packing which enhances the crack tortuosity. The Kc values are in the range 0.215 (0.08) to 0.278 (0.06) MPa m½ and the brittleness index values are in the range 711(19) to 1053(50) m−½

Tracking cocrystallization of active pharmaceutical ingredients with Bbenzoic acid coformer using Broadband Acoustic resonance Dissolution Spectroscopy (BARDS)

This study investigates the use of Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) as a detection method for the formation of cocrystals. BARDS is a novel approach that uses reproducible changes in the compressibility of a solvent as a sample dissolves to characterize and differentiate between materials and in this case cocrystallization. Two cocrystal systems with a 1:1 stoichiometry were examined, which used benzoic acid as a coformer with isonicotinamide and with theophylline. Cocrystals were prepared using dry and wet milling for periods from 1 to 40 min, and samples were analyzed using infrared spectroscopy, powder X-ray diffraction, and BARDS. Comparison of the BARDS data with the IR and PXRD data cross-validated the BARDS results. This study shows that BARDS can be used to rapidly assess the formation of these cocrystals at-line when milling or as a relatively low cost tool in preformulation product development. The data can also be used to gauge the unique entrained gas and gas volume generation of the cocrystal samples during dissolution and their dissolution kinetics