Thermal stability of porous sol-gel phosphosilicates and their surface area stabilisation by lanthanum addition

The thermal stability of porous sol-gel phosphosilicates was studied by comparing the textural features upon calcination between 400 and 550 °C. A significant loss of surface area and pore volume were observed; the first is due to thermal coarsening of the nanoparticles, and the pore volume reduction was ascribed to sintering of the most external nanoparticles producing less void volume. Lanthanum addition was investigated as thermal stabilizer. For the mesoporous phosphosilicate composition, lanthanum addition enhanced the surface area, showing a 45% and 50% improvement with respect to the La-free counterpart; the effect was much less visible for the macroporous composition.

Condensation-enhanced self-assembly as a route to high surface area α-aluminas

High surface area nanosized α-alumina has been obtained by thermally treating a sol-gel-derived mesophase at 1200 C; the mesophase was synthesized by a sol-gel route involving evaporation induced self-assembly (EISA) of a hydrolyzed gel from Al-tri-sec-butoxide in s-BuOH in the presence of a nonionic surfactant (EO20PO70EO20), HCl as catalyst, and water (H2O/Al = 6). The activated material renders moderate surface areas of about 8.4-10 m2 g-1, associated with significant crystallite coarsening. The key aspect to produce smaller crystallites is making the mesophase more resistant to coarsening. This was achieved by enhancing the condensation step by treating the hydrolyzed gel with tetrabutyl ammonium hydroxide (TBAOH) before evaporation. The characteristics of the mesophase indicate condensation of the primary particles with less AlO5 unsaturated sites, at the expense of a lower solid yield due to small crystallites dissolution. The activated TBAOH condensed EISA material is composed of α-alumina aggregated crystallites of about 60-100 nm, and the material possesses surface areas ranging from 16 to 24 m2 g -1 due to the improved resistance to coarsening. At least two aspects are suggested to play a role in this. The worm-hole morphology of the mesophase aggregates yields high particle coordination, which favors densification rather than coarsening. Furthermore, the decrease of the AlO5 defect sites by the TBAOH condensation makes the mesophase less reactive and consequently more resistant to coarsening. © 2013 American Chemical Society.

Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The cytotoxic effects of 6-mercaptopurine (6-MP) were found to be due to drug-derived intracellular metabolites (mainly 6-thioguanine nucleotides and to some extent 6-methylmercaptopurine nucleotides) rather than the drug itself. • Current empirical dosing methods for oral 6-MP result in highly variable drug and metabolite concentrations and hence variability in treatment outcome. WHAT THIS STUDY ADDS • The first population pharmacokinetic model has been developed for 6-MP active metabolites in paediatric patients with acute lymphoblastic leukaemia and the potential demographic and genetically controlled factors that could lead to interpatient pharmacokinetic variability among this population have been assessed. • The model shows a large reduction in interindividual variability of pharmacokinetic parameters when body surface area and thiopurine methyltransferase polymorphism are incorporated into the model as covariates. • The developed model offers a more rational dosing approach for 6-MP than the traditional empirical method (based on body surface area) through combining it with pharmacogenetically guided dosing based on thiopurine methyltransferase genotype. AIMS - To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. METHODS - Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m−2 day−1). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites. RESULTS - The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model. CONCLUSIONS - The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype.

A three dimensional surface measurement and reconstruction system for respiratory function analysis

Respiration is a complex activity. If the relationship between all neurological and skeletomuscular interactions was perfectly understood, an accurate dynamic model of the respiratory system could be developed and the interaction between different inputs and outputs could be investigated in a straightforward fashion. Unfortunately, this is not the case and does not appear to be viable at this time. In addition, the provision of appropriate sensor signals for such a model would be a considerable invasive task. Useful quantitative information with respect to respiratory performance can be gained from non-invasive monitoring of chest and abdomen motion. Currently available devices are not well suited in application for spirometric measurement for ambulatory monitoring. A sensor matrix measurement technique is investigated to identify suitable sensing elements with which to base an upper body surface measurement device that monitors respiration. This thesis is divided into two main areas of investigation; model based and geometrical based surface plethysmography. In the first instance, chapter 2 deals with an array of tactile sensors that are used as progression of existing and previously investigated volumetric measurement schemes based on models of respiration. Chapter 3 details a non-model based geometrical approach to surface (and hence volumetric) profile measurement. Later sections of the thesis concentrate upon the development of a functioning prototype sensor array. To broaden the application area the study has been conducted as it would be fore a generically configured sensor array. In experimental form the system performance on group estimation compares favourably with existing system on volumetric performance. In addition provides continuous transient measurement of respiratory motion within an acceptable accuracy using approximately 20 sensing elements. Because of the potential size and complexity of the system it is possible to deploy it as a fully mobile ambulatory monitoring device, which may be used outside of the laboratory. It provides a means by which to isolate coupled physiological functions and thus allows individual contributions to be analysed separately. Thus facilitating greater understanding of respiratory physiology and diagnostic capabilities. The outcome of the study is the basis for a three-dimensional surface contour sensing system that is suitable for respiratory function monitoring and has the prospect with future development to be incorporated into a garment based clinical tool.

Flow across microvessel walls through the endothelial surface glycocalyx and the interendothelial cleft

A mathematical model is presented for steady fluid flow across microvessel walls through a serial pathway consisting of the endothelial surface glycocalyx and the intercellular cleft between adjacent endothelial cells, with junction strands and their discontinuous gaps. The three-dimensional flow through the pathway from the vessel lumen to the tissue space has been computed numerically based on a Brinkman equation with appropriate values of the Darcy permeability. The predicted values of the hydraulic conductivity Lp, defined as the ratio of the flow rate per unit surface area of the vessel wall to the pressure drop across it, are close to experimental measurements for rat mesentery microvessels. If the values of the Darcy permeability for the surface glycocalyx are determined based on the regular arrangements of fibres with 6nm radius and 8nm spacing proposed recently from the detailed structural measurements, then the present study suggests that the surface glycocalyx could be much less resistant to flow compared to previous estimates by the one-dimensional flow analyses, and the intercellular cleft could be a major determinant of the hydraulic conductivity of the microvessel wall.

Freezing process optimisation of pharmaceutical formulations for freeze drying

The body of work presented in this thesis are in three main parts: [1] the effect of ultrasound on freezing events of ionic systems, [2] the importance of formulation osmolality in freeze drying, and [3] a novel system for increasing primary freeze drying rate. Chapter 4 briefly presents the work on method optimisation, which is still very much in its infancy. Aspects of freezing such as nucleation and ice crystal growth are strongly related with ice crystal morphology; however, the ice nucleation process typically occurs in a random, non-deterministic and spontaneous manner. In view of this, ultrasound, an emerging application in pharmaceutical sciences, has been applied to aid in the acceleration of nucleation and shorten the freezing process. The research presented in this thesis aimed to study the effect of sonication on nucleation events in ionic solutions, and more importantly how sonication impacts on the freezing process. This work confirmed that nucleation does occur in a random manner. It also showed that ultrasonication aids acceleration of the ice nucleation process and increases the freezing rate of a solution. Cryopreservation of animal sperm is an important aspect of breeding in animal science especially for endangered species. In order for sperm cryopreservation to be successful, cryoprotectants as well as semen extenders are used. One of the factors allowing semen preservation media to be optimum is the osmolality of the semen extenders used. Although preservation of animal sperm has no relation with freeze drying of pharmaceuticals, it was used in this thesis to make a case for considering the osmolality of a formulation (prepared for freeze drying) as a factor for conferring protein protection against the stresses of freeze drying. The osmolalities of some common solutes (mostly sugars) used in freeze drying were determined (molal concentration from 0.1m to 1.2m). Preliminary investigation on the osmolality and osmotic coefficients of common solutes were carried out. It was observed that the osmotic coefficient trend for the sugars analysed could be grouped based on the types of sugar they are. The trends observed show the need for further studies to be carried out with osmolality and to determine how it may be of importance to protein or API protection during freeze drying processes. Primary drying is usually the longest part of the freeze drying process, and primary drying times lasting days or even weeks are not uncommon; however, longer primary drying times lead to longer freeze drying cycles, and consequently increased production costs. Much work has been done previously by others using different processes (such as annealing) in order to improve primary drying times; however, these do not come without drawbacks. A novel system involving the formation of a frozen vial system which results in the creation of a void between the formulation and the inside wall of a vial has been devised to increase the primary freeze drying rate of formulations without product damage. Although the work is not nearly complete, it has been shown that it is possible to improve and increase the primary drying rate of formulations without making any modifications to existing formulations, changing storage vials, or increasing the surface area of freeze dryer shelves.

Synthesis of highly efficient and recyclable visible-light responsive mesoporous g-C3N4 photocatalyst via facile template-free sonochemical route

Herein we demonstrate a facile template-free sonochemical strategy to synthesize mesoporous g-C3N4 with a high surface area and enhanced photocatalytic activity. The TEM and nitrogen adsorption–desorption studies confirm mesoporous structure in g-C3N4 body. The photocatalytic activity of mesoporous g-C3N4 is almost 5.5 times higher than that of bulk g-C3N4 under visible-light irradiation. The high photocatalytic performance of the mesoporous g-C3N4 was attributed to the much higher specific surface area, efficient adsorption ability and the unique interfacial mesoporous structure which can favour the absorption of light and separation of photoinduced electron–hole pairs more effectively. A possible photocatalytic mechanism was discussed by the radicals and holes trapping experiments. Interestingly, the synthesized mesoporous g-C3N4 possesses high reusability. Hence the mesoporous g-C3N4 can be a promising photocatalytic material for practical applications in water splitting as well as environmental remediation.