Short cycle times for cost-efficient processing in lyophilized formulations

Pharmaceutical scientists who bulk freeze dry need to foremost identify what quality factors are of a priority during cycle development since the economics of freeze-drying do not allow for both the cost-efficient production and the ability to obtain the highest quality score across all quality factors. Consider; morphology, activity, dissolution, long-term storage, packaging and cost.

Reduced waiting times using a fast switching dual-polarization DDQPSK receiver in a packet switched network

In this paper, we demonstrate a fast switching dual polarization DDQPSK packet switched receiver with very short waiting times. The system employs mth power DDQPSK decoding for high frequency offset tolerance, and Stokes parameter estimation for robust polarization demultiplexing.

Novel formulation strategies for the fabrication of lyophilised orally disintegrating tablets

Orally disintegrating Tablets (ODTs), also known as fast-disintegrating, fast-melt or fast-dissolving tablets, are a relatively novel dosage technology that involves the rapid disintegration or dissolution of the dosage form into a solution or suspension in the mouth without the need for water. The solution containing the active ingredients is swallowed, and the active ingredients are then absorbed through the gastrointestinal epithelium to reach the target and produce the desired effect. Formulation of ODTs was originally developed to address swallowing difficulties of conventional solid oral dosage forms (tablets and capsules) experienced by wide range of patient population, especially children and elderly. The current work investigates the formulation and development of ODTs prepared by freeze drying. Initial studies focused on formulation parameters that influence the manufacturing process and performance of lyophilised tablets based on excipients used in commercial products (gelatin and saccharides). The second phase of the work was followed up by comprehensive studies to address the essential need to create saccharide free ODTs using naturally accruing amino acids individually or in combinations. Furthermore, a factorial design study was carried out to investigate the feasibility of delivering multiparticulate systems of challenging drugs using a novel formulation that exploited the electrostatic associative interaction between gelatin and carrageenan. Finally, studies aimed to replace gelatin with ethically and morally accepted components to the end users were performed and the selected binder was used in factorial design studies to investigate and optimise ODT formulations that incorporated drugs with varies physicochemical properties. Our results show that formulation of elegant lyophilised ODTs with instant disintegration and adequate mechanical strength requires carful optimisation of gelatin concentration and bloom strength in addition to saccharide type and concentration. Successful formulation of saccharides free lyophilised ODTs requires amino acids that crystallise in the frozen state or display relatively high Tg', interact and integrate completely with the binder and, also, display short wetting time with the disintegrating medium. The use of an optimised mixture of gelatin, carrageenan and alanine was able to create viscous solutions to suspend multiparticulate systems and at the same time provide tablets with short disintegration times and adequate mechanical properties. On the other hand, gum arabic showed an outstanding potential for use as a binder in the formulation of lyophilised ODTs. Compared to gelatin formulations, the use of gum arabic simplified the formulation stages, shortened the freeze drying cycles and produced tablets with superior performance in terms of the disintegration time and mechanical strength. Furthermore, formulation of lyophilised ODTs based on gum arabic showed capability to deliver diverse range of drugs with advantages over commercial products.

Oxidation of organic compounds in molten salts

The objective of this research was to investigate the oxidation of organic compounds in molten alkali metal hydroxides containing manganates. It has been shown that controlled oxidation can be readily achieved with high specificity to give products in high yield with very short reaction times. The concurrent changes in the melt were monitored using a vibrating platinum indicator electrode with a quazi-reference electrode which was successfully developed for use in molten (Na-K)OH eutectic at 523K. Henry's Law constants for water in the molten eutectic system (Na-K)OH have been measured and used to calculate the water concentration in the melt. The electrochemistry of manganates in molten (Na-K)OH eutectic at 523K has been studied using the vibrating platinum electrode, and the existence of the species Mn(II), Mn(II!), Mn(IV), Mn(V) and Mn(VI) in such melts has been investigated at various water concentrations. The half-wave potentials of the voltammetric waves were measured versus the cathodic limit of the melt. The stability of Mn(V) or Mn(VI) in the melt was achieved by varying the water concentration. A range of organic chemicals has been passed through molten (Na-K)OH at 523K and the reactions of these chemicals with the melt have been studied. The same organics were then passed through molten (Na-K)OH containing stabilized Mn(V) or Mn{VI) without violent reaction. Methanol, allyl alcohol, propane 1, 2 diol, I-heptene and acetone were oxidized by Mn(V) and Mn(VI). Ethanol was only oxidized by Mn(VI), isopropanol and benzyl alcohol were only oxidized by Mn(V). Npropanol, butanol, 2 methyl propan-2-ol, n-hexane, n-heptane toluene and cyclohexane were unchanged by both Mn(V) and Mn(VI). Detailed experiments have been performed on the reactions of ethanol, iso-propanol and methanol in molten (Na-K)OH containing stabilized Mrt(V) or Mn(VI), and reaction mechanisms have been postulated. Ethanol and iso-propanol were oxidized to acetaldehyde and acetone respectively with a potential for useful chemical process. The oxidation of methanol could be developed as a basis for an industrial methanol disposal process.

The Single drop drying of heat-sensitive materials

The literature relating to the principles and practice of drying of materials, particularly those susceptible to thermal degradation or undesirable loss of volatile components, has been reviewed. Single droplets of heat-sensitive materials were dried whilst suspended in a horizontal wind tunnel from a specially-designed, rotating thermocouple which enabled direct observation of drying behaviour and continuous measurement of droplet temperature as drying progressed. The effects of drying air temperature and initial solids concentration on the potency of various antibiotics, viz. ampicillin, chloramphenicol, oxytetracycline, streptomycin and tetracycline, were assessed using a modified Drug Sensitivity Testing technique. Only ampicillin was heat-sensitive at temperatures above 100°C, e.g. at an air temperature of 115°C its zone diameter was reduced from 100% to 45%. Selected enzymes, viz. dextran sucrase and invertase, were also dried and their residual activities determined by High Performance Liquid Chromatography. The residual activity of dextran sucrase was rapidly reduced at temperatures above 65°C, and the residual activity of invertase reduced rapidly at temperatures above 65°C; but drying with short residence times will retain most of its activity. The performance of various skin-forming encapsulants, viz. rice and wheat starch, dextrin, coffee, skim milk, fructose, gelatine 60 and 150 Bloom, and gum arabic, was evaluated to determine their capabilities for retention of ethanol as a model volatile, under different operating conditions. The effects of initial solids concentration, air velocity and temperature were monitored for each material tested. Ethanol content was analysed by Gas Liquid Chromatography and in some cases dried crusts were removed for examination. Volatiles retention was concluded to depend in all cases upon the rate and nature of the skin formation and selective diffusion phenomena. The results provided further insight into the inter-relationship between temperature, residence time and thermal degradation of heat-sensitive materials. They should also assist in selection of the preferred dryer for such materials, and of the operating parameter to enable maximum retention of the required physico-chemical characteristics in the dried materials.

Applying quantitative methods in the assessment of outcomes of pharmacotherapy of psoriasis

Healthcare providers and policy makers are faced with an ever-increasing number of medical publications. Searching for relevant information and keeping up to date with new research findings remains a constant challenge. It has been widely acknowledged that narrative reviews of the literature are susceptible to several types of bias and a systematic approach may protect against these biases. The aim of this thesis was to apply quantitative methods in the assessment of outcomes of topical therapies for psoriasis. In particular, to systematically examine the comparative efficacy, tolerability and cost-effectiveness of topical calcipotriol in the treatment of mild-to-moderate psoriasis. Over the years, a wide range of techniques have been used to evaluate the severity of psoriasis and the outcomes from treatment. This lack of standardisation complicates the direct comparison of results and ultimately the pooling of outcomes from different clinical trials. There is a clear requirement for more comprehensive tools for measuring drug efficacy and disease severity in psoriasis. Ideally, the outcome measures need to be simple, relevant, practical, and widely applicable, and the instruments should be reliable, valid and responsive. The results of the meta-analysis reported herein show that calcipotriol is an effective antipsoriatic agent. In the short-tenn, the pooled data found calcipotriol to be more effective than calcitriol, tacalcitol, coal tar and short-contact dithranol. Only potent corticosteroids appeared to have comparable efficacy, with less short-term side-effects. Potent corticosteroids also added to the antipsoriatic effect of calcipotriol, and appeared to suppress the occurrence of calcipotriol-induced irritation. There was insufficient evidence to support any large effects in favour of improvements in efficacy when calcipotriol is used in combination with systemic therapies in patients with severe psoriasis. However, there was a total absence of long-term morbidity data on the effectiveness of any of the interventions studied. Decision analysis showed that, from the perspective of the NHS as payer, the relatively small differences in efficacy between calcipotriol and short-contact dithranol lead to large differences in the direct cost of treating patients with mildto-moderate plaque psoriasis. Further research is needed to examine the clinical and economic issues affecting patients under treatment for psoriasis in the UK. In particular, the maintenance value and cost/benefit ratio for the various treatment strategies, and the assessment of patient's preferences has not yet been adequately addressed for this chronic recurring disease.

Multispectral imaging of the ocular fundus using light emitting diode illumination

We present an imaging system based on light emitting diode (LED) illumination that produces multispectral optical images of the human ocular fundus. It uses a conventional fundus camera equipped with a high power LED light source and a highly sensitive electron-multiplying charge coupled device camera. It is able to take pictures at a series of wavelengths in rapid succession at short exposure times, thereby eliminating the image shift introduced by natural eye movements (saccades). In contrast with snapshot systems the images retain full spatial resolution. The system is not suitable for applications where the full spectral resolution is required as it uses discrete wavebands for illumination. This is not a problem in retinal imaging where the use of selected wavelengths is common. The modular nature of the light source allows new wavelengths to be introduced easily and at low cost. The use of wavelength-specific LEDs as a source is preferable to white light illumination and subsequent filtering of the remitted light as it minimizes the total light exposure of the subject. The system is controlled via a graphical user interface that enables flexible control of intensity, duration, and sequencing of sources in synchrony with the camera. Our initial experiments indicate that the system can acquire multispectral image sequences of the human retina at exposure times of 0.05 s in the range of 500-620 nm with mean signal to noise ratio of 17 dB (min 11, std 4.5), making it suitable for quantitative analysis with application to the diagnosis and screening of eye diseases such as diabetic retinopathy and age-related macular degeneration.

Dielectric studies of molecules and intramolecular relaxation processes

A new bridge technique for the measurement of the dielectric absorption of liquids and solutions at microwave frequencies has been described and its accuracy assessed. 'l'he dielectric data of the systems studied is discussed in terms of the relaxation processes contributing to the dielectric absorption and the apparent dipole moments. Pyridine, thiophen and furan in solution have a distribution of relaxation times which may be attributed to the small size of the solute molecules relative to the solvent. Larger rigid molecules in solution were characterized by a single relaxation time as would be anticipated from theory. The dielectric data of toluene, ethyl-, isopropyl- and t-butylbenzene as pure liquids and in solution were described by two relaxation times, one identified with molecular re-orientation and a shorter relaxation time.· The subsequent work was investigation of the possible explanations of this short relaxation process. Comparable short relaxation times were obtained from the analysis of the dielectric data of solutions of p-chloro- and p-bromotoluene below 40°C, o- and m-xylene at 25°C and 1-methyl- and 2 methylnaphthalene at 50 C. Rigid molecules of similar shapes and sizes were characterized by a single relaxation time identified with molecular re-orientation. Contributions from a long relaxation process attributed to dipolar origins were reported for solutions of nitrobenzene, benzonitrile and p-nitrotoluene. A short relaxation process of possible dipolar origins contributed to the dielectric absorption of 4-methyl- and 4-t-butylpyridine in cyclohexane at 25°C. It was concluded that the most plausible explanation of the short relaxation process of the alkyl-aryl hydrocarbons studied appears to be intramolecular relaxation about the alkyl-aryl bond. Finally the mean relaxation times of some phenylsubstituted compounds were investigated to evaluate any shortening due to contributions from the process of relaxation about the phenyl-central atom bond. The relaxation times of triphenylsilane and phenyltrimethylsilane were significantly short.

The performance of poly(styrene)-block-poly(2-vinyl pyridine)-block- poly(styrene) triblock copolymers as pH-driven actuators

Poly(styrene)-block-poly(2-vinyl pyridine)-block-poly(styrene) (PS-b-P2VP-b-PS) triblock copolymers were synthesised by anionic polymerisation. Thick films were cast from solution and their structure analysed by small angle X-ray scattering (SAXS). Longer annealing times led to more ordered structures whereas short evaporation times effectively "lock" the polymer chains in a disordered state by vitrification. Well-ordered structures not only provide an isotropic network, which reduces localised stress within the material, but are also essential for fundamental studies of soft matter because their activity on the molecular scale must be analysed and understood prior to their use in technological applications. Well-characterised PS-b-P2VP-b-PS materials have been coupled to a pH-oscillating reaction and their potential application as responsive actuators is discussed. This journal is © The Royal Society of Chemistry.

Immunological synapse: a mathematical model of the bond formation process:mathematical modelling of the immature synapse

The cell:cell bond between an immune cell and an antigen presenting cell is a necessary event in the activation of the adaptive immune response. At the juncture between the cells, cell surface molecules on the opposing cells form non-covalent bonds and a distinct patterning is observed that is termed the immunological synapse. An important binding molecule in the synapse is the T-cell receptor (TCR), that is responsible for antigen recognition through its binding with a major-histocompatibility complex with bound peptide (pMHC). This bond leads to intracellular signalling events that culminate in the activation of the T-cell, and ultimately leads to the expression of the immune eector function. The temporal analysis of the TCR bonds during the formation of the immunological synapse presents a problem to biologists, due to the spatio-temporal scales (nanometers and picoseconds) that compare with experimental uncertainty limits. In this study, a linear stochastic model, derived from a nonlinear model of the synapse, is used to analyse the temporal dynamics of the bond attachments for the TCR. Mathematical analysis and numerical methods are employed to analyse the qualitative dynamics of the nonequilibrium membrane dynamics, with the specic aim of calculating the average persistence time for the TCR:pMHC bond. A single-threshold method, that has been previously used to successfully calculate the TCR:pMHC contact path sizes in the synapse, is applied to produce results for the average contact times of the TCR:pMHC bonds. This method is extended through the development of a two-threshold method, that produces results suggesting the average time persistence for the TCR:pMHC bond is in the order of 2-4 seconds, values that agree with experimental evidence for TCR signalling. The study reveals two distinct scaling regimes in the time persistent survival probability density prole of these bonds, one dominated by thermal uctuations and the other associated with the TCR signalling. Analysis of the thermal fluctuation regime reveals a minimal contribution to the average time persistence calculation, that has an important biological implication when comparing the probabilistic models to experimental evidence. In cases where only a few statistics can be gathered from experimental conditions, the results are unlikely to match the probabilistic predictions. The results also identify a rescaling relationship between the thermal noise and the bond length, suggesting a recalibration of the experimental conditions, to adhere to this scaling relationship, will enable biologists to identify the start of the signalling regime for previously unobserved receptor:ligand bonds. Also, the regime associated with TCR signalling exhibits a universal decay rate for the persistence probability, that is independent of the bond length.

Accommodation in young adults wearing multifocal soft contact lenses under long- and short- wavelength lighting

Purpose: Several studies have suggested accommodative lags may serve as a stimulus for myopic growth, and while a blurred foveal image is believed to the main stimulus for accommodation, spectral composition of the retinal image is also believed to influence accommodative accuracy. Of particular interest is how altering spectral lighting conditions influences accommodation in the presence of soft multifocal contact lenses, which are currently being used off-label for myopia control. Methods: Accommodative responses were assessed using a Grand Seiko WAM-5500 autorefractor for four target distances: 25, 33, 50, and 100cm for 30 young adult subjects (14 myopic, 16 emmetropic; mean refractive errors (±SD, D) -4.22±2.04 and -0.15±0.67 respectively). Measurements were obtained with four different soft contact lenses, Single vision distance (SVD), Single vision near (SVN), Centre-Near (CN) and Centre-Distance (CD) (+1.50 add), and three different lighting conditions: red (peak λ 632nm), blue (peak λ 460nm), and white (peak λ 560nm). Corrections for chromatic differences in refraction were made prior to calculating accommodative errors. Results: The size of accommodative errors was significantly affected by lens design (p<0.001), lighting (p=0.027), and target distance (p=0.009). Mean accommodative errors were significantly larger with the SV lenses compared to the CD and CN designs (p<0.001). Errors were also significantly larger under blue light compared to white (p=0.004) and a significant interaction noted between lens design and lighting (p<0.001). Blue light generally decreased accommodative lags and increased accommodative leads relative to white and red light, the opposite was true of red light (p≤0.001). Lens design also significantly influenced direction of accommodative error (i.e. lag or lead) (p<0.001). Interactions with or between refractive groups were not found to be statistically significant for either the magnitude or direction of accommodative error (p>0.05 for all). Conclusions: Accuracy of accommodation is affected by both lens design and by wavelength of lighting. These accommodative lag data lend some support to recent speculation about the potential therapeutic value of lighting with a spectral bias towards blue during near work for myopia, although such treatment effects are likely to be more subtle under broad compared to the narrow spectrum lighting conditions used here.

Conjunctival epithelial flaps with 18 months of silicone hydrogel contact lens wear

Purpose. To report differences in the incidence of conjunctival epithelial flaps (CEFs) found in a group of neophyte contact wearers using two different silicone hydrogel contact lenses on a daily- and continuous-wear basis during an 18-month period. Methods. Sixty-one subjects were initially examined, and 53 were eligible to participate in the study. Eligible subjects were randomly assigned to wear one of two silicone hydrogel materials, lotrafilcon A or balafilcon A, on a daily- or continuous-wear basis. After an initial screening, subjects were monitored weekly for the first month and then after 3, 6, 12, and IS months. The incidence of CEFs in each of the four contact lens groups was recorded. Results. Five of the 53 subjects enrolled in the study showed bilateral CEFs. A higher incidence of CEFs was found in subjects wearing lotrafilcon A lenses (n = 4) compared to balafilcon A lenses (it = 1) (chi(2) = 4.37, P=0.04). Differences in the incidence of CEFs between subjects wearing lenses on a daily-wear basis (n = 1) versus a continuous-wear basis (it = 4) showed a weak statistical significance (chi(2) = 3.03, P=0.08). Conclusions. Lotrafilcon A lenses were associated with a higher incidence of CEFs than balafilcon A lenses were, and this difference may be attributed to differences in the edge design, material, or modulus of rigidity between the two lens types. Subjects wearing lenses on a daily-wear basis showed fewer adverse events than did subjects wearing lenses on a continuous-wear basis. The longer wearing times of subjects wearing lenses on a continuous-wear basis are likely to exacerbate the incidence of CEFs.

Computational mechanics of molecular systems:quantifying high-dimensional dynamics by distribution of Poincaré recurrence times

A framework that connects computational mechanics and molecular dynamics has been developed and described. As the key parts of the framework, the problem of symbolising molecular trajectory and the associated interrelation between microscopic phase space variables and macroscopic observables of the molecular system are considered. Following Shalizi and Moore, it is shown that causal states, the constituent parts of the main construct of computational mechanics, the e-machine, define areas of the phase space that are optimal in the sense of transferring information from the micro-variables to the macro-observables. We have demonstrated that, based on the decay of their Poincare´ return times, these areas can be divided into two classes that characterise the separation of the phase space into resonant and chaotic areas. The first class is characterised by predominantly short time returns, typical to quasi-periodic or periodic trajectories. This class includes a countable number of areas corresponding to resonances. The second class includes trajectories with chaotic behaviour characterised by the exponential decay of return times in accordance with the Poincare´ theorem.

Analytical techniques for the study of soft contact lens spoilation

Soft contact lens wear has become a common phenomenon in recent times. The contact lens when placed in the eye rapidly undergoes change. A film of biological material builds up on and in the lens matrix. The long term wear characteristics of the lens ultimately depend on this process. With time distinct structures made up of biological material have been found to build up on the lens. A fuller understanding of this process and how it relates to the lens chemistry could lead to contact lenses that are better tolerated by the eye. The tear film is a complex biological fluid, it is this fluid that bathes the lens during wear. It is reasonable to suppose that it is material derived from this source that accumulates on the lens. To understand this phenomenon it was decided to investigate the make up and conformation of the protein species that are found on and in the lens. As inter individual variations in tear fluid composition have been found it is important to be able to study the proteins on a single lens. Many of the analytical techniques used in bio research are not suitable for this study because of the lack of sensitivity. Work with poly acrylamide electrophoresis showed the possibility of analyzing the proteins extracted from a single lens. The development of a biotin avidin electro-blot and an enzyme linked aniibody electro-blot, lead to the high sensitivity detection and identification of the proteins present. The extraction of proteins from a lens is always incomplete. A method that analyses the proteins in situ would be a great advancement. Fourier transform infra red microscopy was developed to a point where a thin section of a contact lens could yield information about the proteins present and their conformation. The three dimensional structure of the gross macroscopic structures termed white spots was investigated using confocal laser microscopy.

Regional differences in oxygen saturation in retinal arterioles and venules

BACKGROUND: Retinal vessel oxygenation saturation measurements have been the focus of much attention in recent years as a potential diagnostic parameter in a number of ocular and systemic pathologies. This interest has been heightened by the ability to measure oxygen saturation in vivo using a photographic technique. METHODS: Retinal vessel oxygenation in venules and arterioles of 279 retinal vessels of 12 healthy Caucasian participants (mean age: 30 SD (+/- 6) years) were measured consecutively three times to evaluate short-term variation in oxygen saturation and regional variability of retinal vessel oxygen saturation using dual-wavelength technology (Oxymetry Modul, Imedos, Germany). All subjects underwent standard optometric assessment including non-contact intra-ocular pressure assessment as well as having their systemic blood pressure measured. RESULTS: Vessels were grouped as either near-macula or peripheral, depending on their location. Peripheral arterioles and venules exhibited significantly lower oxygen saturation compared to their near-macula counterparts (arterioles: 94.7% (SD 3.9) vs. 99.7% (SD 3.2); venules: 65.1% (SD 7.2) vs. 90.3% (SD 6.7)). Both arterioles and venules, main branches, and those feeding and draining the retina near the macula and periphery showed low short-term variability of oxygen saturation (arterioles: COV 1.2-1.8%; venules: COV 2.9-4.9%). CONCLUSIONS: Retinal arterioles and venules exhibit low short-term variation of oxygen saturation in healthy subjects. Regional differences in oxygen saturation could be a potential useful marker for risk stratification and diagnostic purposes of area-specific retinal pathology such as age-related macula degeneration and diabetic maculopathy.