Excipient characterization and particle engineering to develop directly compressed orally disintegrating tablets

ODTs have emerged as a novel oral dosage form with a potential to deliver a wide range of drug candidates to paediatric and geriatric patients. Compression of excipients offers a costeffective and translatable methodology for the manufacture of ODTs. Though, technical challenges prevail such as difficulty to achieve suitable tablet mechanical strength while ensuring rapid disintegration in the mouth, poor compressibility of preferred ODT diluent Dmannitol, and limited use for modified drug-release. The work investigates excipients’ functionality in ODTs and proposes new methodologies for enhancing material characteristics via process and particle engineering. It also aims to expand ODT applications for modified drug-release. Preformulation and formulation studies employed a plethora of techniques/tests including AFM, SEM, DSC, XRD, TGA, HSM, FTIR, hardness, disintegration time, friability, stress/strain and Heckel analysis. Tableting of D-mannitol and cellulosic excipients utilised various compression forces, material concentrations and grades. Engineered D-mannitol particles were made by spray drying mannitol with pore former NH4HCO3. Coated microparticles of model API omeprazole were prepared using water-based film forming polymers. The results of nanoscopic investigations elucidated the compression profiles of ODT excipients. Strong densification of MCC (Py is 625 MPa) occurs due to conglomeration of physicomechanical factors whereas D-mannitol fragments under pressure leading to poor compacts. Addition of cellulosic excipients (L-HPC and HPMC) and granular mannitol to powder mannitol was required to mechanically strengthen the dosage form (hardness >60 N, friability <1%) and to maintain rapid disintegration (<30 sec). Similarly, functionality was integrated into D-mannitol by fabrication of porous, yet, resilient particles which resulted in upto 150% increase in the hardness of compacts. The formulated particles provided resistance to fracture under pressure due to inherent elasticity while promoted tablet disintegration (50-77% reduction in disintegration time) due to porous nature. Additionally, coated microparticles provided an ODT-appropriate modified-release coating strategy by preventing drug (omeprazole) release.

Determining the contribution of technical change, efficiency change and scale change to productivity growth in the privatized English and Welsh water and sewerage industry:1985-2000

The water and sewerage industry of England and Wales was privatized in 1989 and subjected to a new regime of environmental, water quality and RPI+K price cap regulation. This paper estimates a quality-adjusted input distance function, with stochastic frontier techniques in order to estimate productivity growth rates for the period 1985-2000. Productivity is decomposed so as to account for the impact of technical change, efficiency change, and scale change. Compared with earlier studies by Saal and Parker [(2000) Managerial Decision Econ 21(6):253-268, (2001) J Regul Econ 20(1): 61-90], these estimates allow a more careful consideration of how and whether privatization and the new regulatory regime affected productivity growth in the industry. Strikingly, they suggest that while technical change improved after privatization, productivity growth did not improve, and this was attributable to efficiency losses as firms appear to have struggled to keep up with technical advances after privatization. Moreover, the results also suggest that the excessive scale of the WaSCs contributed negatively to productivity growth. © 2007 Springer Science+Business Media, LLC.

The comparative impact of privatisation and regulation on productivity growth in the English and Welsh water and sewerage industry, 1985-99

After the 10 regional water authorities of England and Wales were privatized in November 1989, the successor WASCs (water and sewerage companies) faced a new regulatory regime that was designed to promote productivity growth while simultaneously improving drinking water and environmental quality. As legally mandated quality improvements necessitated a costly capital investment programme, the industry's economic regulator – the Office of Water Services – implemented a RPI + K pricing system, designed to compensate the WASCs for their capital investment programme while also encouraging faster rates of productivity growth. This paper considers the relative effects of privatization and regulation on productivity growth in the industry using both non-parametric and parametric methods to provide a crosscheck on the robustness of the results. While there is evidence that labour productivity improved after privatization, there is no evidence that privatization led to a growth in TFP (total factor productivity). However, there is some evidence of a small increase in the rate of TFP growth in the aftermath of a substantial tightening of the regulatory regime that took place in 1995. These results, therefore, are consistent with evidence from other research that privatization, in the absence of effective competition and/or regulation, is not necessarily associated with improved economic performance.

Productivity and price performance in the privatized water and sewerage companies of England and Wales

After its privatization in 1989, the water and sewerage industry of England and Wales faced a new regulatory régime and implemented a substantial capital investment program aimed at improving water and environmental standards. A new RPI + K regulatory pricing system was designed to compensate the industry for its increased capital costs, encourage increased efficiency, and maintain fair prices for customers. This paper evaluates how successful privatization and the resulting system of economic regulation has been. Estimates of productivity growth, derived with quality adjusted output indices, suggest that despite reductions in labor usage, total factor productivity growth has not improved since privatization. Moreover, total price performance indices reveal that increases in output prices have outstripped increases in input costs, a trend which is largely responsible for the increase in economic profits that has occurred since privatization. * We would like to thank Emmanuel Thanassoulis, Joshy Easaw, Jim Love, John Sawkins, and an anonymous referee for helpful comments on earlier drafts of this paper. The usual disclaimer applies.

An investigation of thin amorphous carbon-based sputtered coatings for MEMS and micro-engineering applications

The work presented in this thesis describes an investigation into the production and properties of thin amorphous C films, with and without Cr doping, as a low wear / friction coating applicable to MEMS and other micro- and nano-engineering applications. Firstly, an assessment was made of the available testing techniques. Secondly, the optimised test methods were applied to a series of sputtered films of thickness 10 - 2000 nm in order to: (i) investigate the effect of thickness on the properties of coatingslcoating process (ii) investigate fundamental tribology at the nano-scale and (iii) provide a starting point for nanotribological coating optimisation at ultra low thickness. The use of XPS was investigated for the determination of Sp3/Sp2 carbon bonding. Under C 1s peak analysis, significant errors were identified and this was attributed to the absence of sufficient instrument resolution to guide the component peak structure (even with a high resolution instrument). A simple peak width analysis and correlation work with C KLL D value confirmed the errors. The use of XPS for Sp3/Sp2 was therefore limited to initial tentative estimations. Nanoindentation was shown to provide consistent hardness and reduced modulus results with depth (to < 7nm) when replicate data was suitably statistically processed. No significant pile-up or cracking of the films was identified under nanoindentation. Nanowear experimentation by multiple nanoscratching provided some useful information, however the conditions of test were very different to those expect for MEMS and micro- / nano-engineering systems. A novel 'sample oscillated nanoindentation' system was developed for testing nanowear under more relevant conditions. The films were produced in an industrial production coating line. In order to maximise the available information and to take account of uncontrolled process variation a statistical design of experiment procedure was used to investigate the effect of four key process control parameters. Cr doping was the most significant control parameter at all thicknesses tested and produced a softening effect and thus increased nanowear. Substrate bias voltage was also a significant parameter and produced hardening and a wear reducing effect at all thicknesses tested. The use of a Cr adhesion layer produced beneficial results at 150 nm thickness, but was ineffective at 50 nm. Argon flow to the coating chamber produced a complex effect. All effects reduced significantly with reducing film thickness. Classic fretting wear was produced at low amplitude under nanowear testing. Reciprocating sliding was produced at higher amplitude which generated three body abrasive wear and this was generally consistent with the Archard model. Specific wear rates were very low (typically 10-16 - 10-18 m3N-1m-1). Wear rates reduced exponentially with reduced film thickness and below (approx.) 20 nm, thickness was identified as the most important control of wear.