In situ conjugation of dithiophenol maleimide polymers and oxytocin for stable and reversible polymer–peptide conjugates

The in situ one-pot synthesis of peptide–polymer bioconjugates is reported. Conjugation occurs efficiently without the need for purification of dithiophenol maleimide functionalized polymer as a disulfide bridging agent for the therapeutic oxytocin. Conjugation of polymers was demonstrated to be reversible and to significantly improve the solution stability of oxytocin

The influence of solid state information and descriptor selection on statistical models of temperature dependent aqueous solubility.

Predicting the equilibrium solubility of organic, crystalline materials at all relevant temperatures is crucial to the digital design of manufacturing unit operations in the chemical industries. The work reported in our current publication builds upon the limited number of recently published quantitative structure-property relationship studies which modelled the temperature dependence of aqueous solubility. One set of models was built to directly predict temperature dependent solubility, including for materials with no solubility data at any temperature. We propose that a modified cross-validation protocol is required to evaluate these models. Another set of models was built to predict the related enthalpy of solution term, which can be used to estimate solubility at one temperature based upon solubility data for the same material at another temperature. We investigated whether various kinds of solid state descriptors improved the models obtained with a variety of molecular descriptor combinations: lattice energies or 3D descriptors calculated from crystal structures or melting point data. We found that none of these greatly improved the best direct predictions of temperature dependent solubility or the related enthalpy of solution endpoint. This finding is surprising because the importance of the solid state contribution to both endpoints is clear. We suggest our findings may, in part, reflect limitations in the descriptors calculated from crystal structures and, more generally, the limited availability of polymorph specific data. We present curated temperature dependent solubility and enthalpy of solution datasets, integrated with molecular and crystal structures, for future investigations

Thermal analysis of chiral drug mixtures: the DSC behavior of mixtures of ephedrine HCl and pseudoephedrine HCl enantiomers

A method for peak shape analysis and deconvolution of overlapping endotherms in differential scanning calorimetry (DSC) data has been previously reported. In this study the method is applied to binary mixtures of, (i) (1S,2S)-(+)- and (1R,2R)-(-)-ψ-ephedrine HCl, and (ii) (1S,2S)-(+)-ψ-ephedrine HCl and its diastereomer, (1S,2R)-(+)-ephedrine HCl. Phase diagrams based on enthalpies of fusion at the melting point (ΔH ) as a function of mol% composition are linear. However, the phase diagrams based on melting temperature as a function of mol% composition are non-linear and show deviations from the theoretical Prigogine-Defay and Schröder-van Laar equations. Estimates of eutectic compositions are more definitive from the diagrams based on ΔH values. The phase diagram for the ψ-ephedrine HCl enantiomers demonstrates racemic compound formation with eutectic points for the compound and the pure enantiomers at 28.1 ± 2.5 mol% and 71.9 ± 2.5 mol%. The ΔH phase diagram for mixtures of (1S,2R)-(+)-ephedrine HCl and (1S,2S)-(+)-ψ-ephedrine HCl suggested the formation of a weak complex with a composition close to 60 mol% of the (1S,2S)-(+)-isomer

Physicochemical compatibility of propofol with thiopental sodium

The physicochemical compatibility of propofol and thiopental sodium when mixed together in various ratios and stored was studied. Mixtures of propofol and thiopental sodium in five volume ratios from 1:3 to 3:1 were refrigerated (4 °C) for up to seven days and then centrifuged at 2000g for two hours. Droplet sizes were determined at intervals by optical microscopy and laser diffraction, and chemical stability of the 1:1 mixture was evaluated by high- performance liquid chromatography (HPLC). Optical microscopy and laser diffraction indicated negligible changes in droplet size within 48 hours of mixing. A small increase in the width of the frequency distribution of droplet sizes occurred 24-48 hours after mixing for the two mixtures with the lowest propofol concentration. Some coalescence of droplets occurred on centrifugation. These results indicated negligible formation of droplets that might cause embolism after i.v. injection of fresh mixtures (not more than six hours old). A yellow color appearing after 24-48 hours indicated anticipated chemical changes. HPLC of samples stored at 25 °C indicated clinically unimportant drug loss after six hours. The mixtures were considered physically stable for not more than 48 hours. Droplet size in mixtures of propofol and thiopental sodium did not increase until at least 24 hours. Drug loss from mixtures containing propofol 5 mg/mL and thiopental sodium 12.5 mg/mL was insignificant for up to eight hours

Propofol-thiopentone admixture: recovery characteristics

We have investigated in a prospective double-blind study, recovery from anaesthesia induced by two admixtures of propofol and thiopentone and compared it with a third group of patients who received propofol and lignocaine, Ninety unpremedicated ASA 1 or 2 patients scheduled for elective gynaecological laparoscopy as a daycase procedure were randomly allocated to receive one of three different mixtures for induction of anaesthesia as part of a standardized anaesthetic: Group P-50: propofol 1% 10 ml/thiopentone 2.5% 10 ml, Group P-75: propofol 1% 15 ml/thiopentone 2.5% 5 ml, Group P-100: propofol 1% 20 ml/lignocaine 1% 4 mi Recovery from anaesthesia was assessed for up to four hours post-induction by critical flicker fusion threshold and best post-box toy completion time. Comparison was made with preoperative baseline performance, There was no significant difference in postoperative recovery between the three groups with either assessment but no group returned to their mean preoperative performance levels within the first four hours post-induction. Nor was there any difference between the groups with respect to postoperative analgesia or anti-emetic administration Utilizing the most sensitive end-point, a sample of nearly 1000 patients in each group would be required to confirm the observed difference with a power of 0.8 based on the data from this study. In comparison with lignocaine, the addition of thiopentone to propofol does not delay recovery from anaesthesia and does not increase postoperative analgesic or anti-emetic requirements

Biodegradable implants for the delivery of veterinary vaccines: Design, manufacture and antibody responses in sheep

Biodegradable implants made from cholesterol and lecithin (C:L) were used to deliver a recombinant antigen (recombinant Dichelobacter nodosus pili) and adjuvant (Quil A) to sheep. Implants (5.5-x1.8-mm) were placed subcutaneously and compared to a conventional vaccination regime (2 injections, 4 weeks apart) for antibody responses and tissue compatibility. Release profiles of antigen and adjuvant were also studied in vitro and in vivo. The presence of Quil A in vaccine implants had a marked effect on the rate at which antigen was released with 29 and 44% being released in the first 24 h from implants containing pili alone and pili with Quil A, respectively. Sheep produced significant levels of antibody when immunized with implants, however the response was short-lived and of significantly lower intensity than the response stimulated by two injections of antigen with Quil A (