Analysis of laboratory and field measurements of directionally spread nonlinear ocean waves

Surface gravity waves exist in the oceans as multi-directional nonlinear phenomena. Understanding how these two properties interact is intrinsically important in itself. Furthermore, an understanding of this relationship may be used to gain insight into other oceanic phenomena. This thesis first describes an experimental investigation into the relationship between directionality and non-linearity (Part I). This relationship was then used as a tool to estimate the directional spreading of field data (Part II). Experiments have been conducted in which directionally spread focused wave groups were created in a wave tank. The relationship between the degree of directional spreading and the second-order bound harmonics of the wave groups was examined, in particular the formation of a `set-up'. These measurements were then compared to predictions from second-order theories, finding good agreement. The two-dimensional structure of the bound waves was explored giving new insight into the underlying physics. Experiments were then carried out for directionally spread crossing wave groups. It is believed that the crossing of two sufficiently separated wave groups may be the cause of an anomalous set-up in the second-order bound waves observed for some extreme and potentially freak waves. This set-up is reproduced experimentally. Again, the results of these test agreed very well when compared to second-order theory. The insight gained from the foregoing experiments was then utilised in the analysis of field data. A method, which requires only a single measurement to estimate the observed degree of directional spreading, was applied to a large dataset of field measurements from the North Alwyn platform in the North Sea. This method was then compared to conventional approaches, which require multiple concurrent measurements. The method that requires only a single measurement was shown to be effective, and presents a promising approach to gaining additional insight about the directional spreading of point observations

Gastrointestinal diseases and their impact on drug solubility:Crohn's disease

In order to investigate differences in drug solubilisation and dissolution in luminal fluids of Crohn's disease (CD) patients and healthy subjects, biorelevant media representative of CD patients were developed using information from literature and a Design of Experiment (DoE) approach. The CD media were characterised in terms of surface tension, osmolality, dynamic viscosity and buffer capacity and compared to healthy biorelevant media. To identify which drug characteristics are likely to present a high risk of altered drug solubility in CD, the solubility of six drugs was assessed in CD media and solubility differences were related to drug properties. Identified differences in CD patients compared to healthy subjects were a reduced concentration of bile salts, a higher gastric pH and a higher colonic osmolality. Differences in the properties of CD compared to healthy biorelevant media were mainly observed for surface tension and osmolality. Drug solubility of ionisable compounds was altered in gastric CD media compared to healthy biorelevant media. For drugs with moderate to high lipophilicity, a high risk of altered drug solubilisation in CD is expected, since a significant negative effect of log P and a positive effect of bile salts on drug solubility in colonic and fasted state intestinal CD media was observed. Simulating the conditions in CD patients in vitro offers the possibility to identify relevant differences in drug solubilisation without conducting expensive clinical trials.</p

Gastrointestinal diseases and their impact on drug solubility:Ulcerative Colitis

For poorly soluble compounds, drug product performance in patients with Ulcerative Colitis (UC) compared to healthy subjects can be affected due to differences in drug solubility in GI fluids. A risk assessment tool was developed to identify compounds with a high risk of altered solubility in the GI fluids of UC patients. Pathophysiological changes impacting on the composition of GI fluids in UC patients were considered and UC biorelevant media representative of the stomach, intestine and colon were developed based on biorelevant media based on healthy subjects and literature data using a Design of Experiment approach. The UC media were characterised and revealed differences in surface tension, osmolality and buffer capacity compared to media based on healthy subjects. The solubility of six drugs was investigated in UC biorelevant media and results were related to media- and drug-dependent factors. A lower drug solubility in UC intestinal media was observed for compounds with a high lipophilicity. In UC simulated colonic fluids, drug solubility was altered for ionisable compounds. Additionally, a higher solubility of neutral lipophilic drugs was observed in UC fasted state colonic media with increased concentrations of soluble proteins. The developed UC biorelevant media offer the possibility to identify the risk of altered drug solubilisation in UC patients without conducting expensive clinical trials. A high risk was related to drug ionization properties and lipophilicity in the current study with all investigated drugs showing differences in solubility in biorelevant media based on UC patients compared to healthy subjects.</p

Gastrointestinal diseases and their impact on drug solubility:Celiac disease

The aim of this study was to develop an in vitro tool for predicting drug solubility and dissolution in intestinal fluids of patients with Celiac disease (CED). Biorelevant media for patients with CED were developed based on published information and a Design of Experiment (DoE) approach. The CED biorelevant media were characterised according to their surface tension, osmolality, dynamic viscosity and buffer capacity. By performing solubility studies of six drugs with different physicochemical properties in CED media, we aimed to identify drugs at high risk of altered luminal solubility in CED patients. Identified differences in CED patients compared to healthy subjects were related to a higher concentration of bile salts, lecithin and cholesterol and included as factors in the DoE resulting in 8 CED biorelevant media. Differences in media properties were observed for the surface tension between biorelevant media based on CED patients and healthy subjects. In terms of solubility, only a minimal effect of CED on the solubility of the hydrophilic neutral compound azathioprine was observed. For neutral moderately lipophilic compounds (budesonide, celecoxib), a higher surfactant concentration resulted in most cases in a higher drug solubility, while it was specific to each drug whether this was mainly driven by bile salts or lecithin. In comparison, drug solubilisation of ionisable compounds with moderate to high lipophilicity was less impacted by CED differences. The developed biorelevant CED media serve as in vitro tool to identify the main media factors impacting on drug solubility.</p

Experimental Observation of Modulational Instability in Crossing Surface Gravity Wavetrains

The coupled nonlinear Schrödinger equation (CNLSE) is a wave envelope evolution equation applicable to two crossing, narrow-banded wave systems. Modulational instability (MI), a feature of the nonlinear Schrödinger wave equation, is characterized (to first order) by an exponential growth of sideband components and the formation of distinct wave pulses, often containing extreme waves. Linear stability analysis of the CNLSE shows the effect of crossing angle, θ, on MI, and reveals instabilities between 0◦ < θ < 35◦, 46◦ < θ < 143◦, and 145◦ < θ < 180◦. Herein, the modulational stability of crossing wavetrains seeded with symmetrical sidebands is determined experimentally from tests in a circular wave basin. Experiments were carried out at 12 crossing angles between 0◦ ≤ θ ≤ 88◦, and strong unidirectional sideband growth was observed. This growth reduced significantly at angles beyond θ ≈ 20◦, reaching complete stability at θ = 30–40◦. We find satisfactory agreement between numerical predictions (using a time-marching CNLSE solver) and experimental measurements for all crossing angles