Oral drug administration remains the most popular route of drug delivery. Absorption of the dissolved drug through the intestinal epithelial membrane is a prerequisite to systemic bioavailability and drug efficacy. In efforts to reduce the long lead times, attrition rates, and costs of drug discovery and development, computational models have been developed to predict the membrane permeability and absorption efficiency of a dosed drug. Many models utilize various molecular descriptors to correlate with in vitro permeability or human intestinal absorption data. It is widely accepted that the two most significant physicochemical properties that control a compound's passive transport process are its aqueous solubility and lipophilicity characteristics.This work will discuss the theoretical background of passive transport, a number of computational models developed to predict in vitro permeability, other models that predict human fraction of dose absorbed, and predicting absorption efficiency relative to a maximum dose. A newly developed prediction method is also presented, that reveals an interesting relationship between fraction absorbed and the melting point of the drug.

Three solution models: ideal, regular, and quasi- regular, were used to predict the melting point of eutectic mixtures containing Polyethylene Glycol (PEG) 400 and PEG 4000 with nine poorly water- soluble drugs: 1-naphthoic acid, estrone, griseofulvin, indomethacin, phenobarbital, paracetamol, salicylic acid, salicylamide and naproxen. PEG 400 was physically mixed with drug at different weight percentages to determine the melting points of the pure drugs and the melting point depression using Differential Scanning Calorimetry (DSC). The PEG 4000 eutectic mixtures were processed by the solvent evaporation method. In both the PEG 400 and PEG 4000 study, the quasi-regular solution model accounted for the most realistic conditions of entropy and enthalpy of the mixtures compared to ideal and regular solution models.

The UPPER (Unified Physicochemical Property Estimation Relationships) model uses additive and non-additive parameters to estimate 21 biologically and environmentally important physicochemical properties of organic compounds. Thermodynamically sound relationships are used to predict boiling and melting points, aqueous and octanol solubilities, vapor pressure and the air-octanol, air-water and octanol-water partition coefficients. These properties determine the distribution and fate of organic compounds in biological and environmental systems. The model has been validated on a data set of 2000 hydrocarbons and polyhalogenated hydrocarbons, provides a simple and accurate method to predict the properties studied.

Melting point finds applications in chemical identification, purification and in the calculation of a number of other physicochemical properties such as vapor pressure and aqueous solubility. Despite the availability of enormous amounts of experimental data, no generally applicable methods have been developed to estimate the melting point of a compound from its chemical structure. A quick estimation of melting point can be a useful tool in the design of new chemical entities.In this dissertation, a simple means of estimating the melting points for a large variety of pharmaceutically and environmentally relevant organic compounds is developed. Melting points are predicted from the separate calculation of the enthalpy and entropy of melting directly from the chemical structure. The entropy of melting is calculated using a semi-empirical equation based on only two non-additive molecular parameters. This equation is validated and refined using a large collection of experimental entropy of melting values. The enthalpy of melting is calculated by additive group contributions.Melting points are estimated from the ratio of the enthalpy of melting and the entropy of melting. All of the methods and group contributions developed in this study are compatible with the UPPER (Unified Physical Property Estimating Relationships) scheme. The predicted melting points are compared to experimental melting points for over 2200 organic compounds collected from the literature. The average absolute error in melting point prediction is 30.1 °. This is a very reasonable estimate considering the size and diversity of the dataset used in this study.

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Evidence indicates seed oil melting point is likely an adaptive quantitative trait in many flowering plant species. An adaptive hypothesis suggests selection has changed the melting point of seed oils to covary with germination temperatures because of a trade-off between total energy stores and the rate of energy acquisition during germination under competition. The predicted differences in relative fitness under different temperatures have not yet been tested and little is known about the genetic basis of differences in oil composition. I used Arabidopsis thaliana to: (1) assess the fitness consequences of high and low melting point seeds germinating at different temperatures, (2) assess what genes underlie natural variation in seed oil composition, and (3) consider how these genes may be used to create oils with particular characteristics. To assess the effects of seed oil melting point on timing of seedling emergence and fitness, I competed high and low melting point lines of A. thaliana under cold and warm temperatures. Emergence timing between these lines was not significantly different at either temperature, which comported with warm temperature predictions but not cold temperature predictions. Under all conditions, plants competing against high melting point lines had lower fitness relative to those against low melting point lines, which matched expectations for undifferentiated emergence times. To assess the genetic basis of naturally occurring variation in seed oil melting point, the seed oil compositions of 391 accessions of A. thaliana were used in a genome-wide association study. Twelve genes were tightly linked with SNPs significantly associated with seed oil melting point variation. Seven encoded lipid synthesis enzymes or regulatory products. The remaining 5 encoded products with no clear relation to seed oil melting point. Results suggest selection can alter quantitative trait variation in response to local conditions through a small set of genes. 268 seed-expressed, candidate genes were linked to 103 SNPs associated with A. thaliana seed oil fatty acids. Eight genes were involved in lipid metabolism, and thirty-four encoded regulatory products. I discuss how knowledge of these genes can be used to breed and engineer desirable oil compositions for industry and nutrition. / text

The state of the art in artificial micro self assembly concepts are reviewed. The history of assembly is presented with a comparison to macro assembly, which has been widely studied, and micro self assembly. Criteria were developed and tested to show that macro assembly is more complex in ways that micro self assembly is not. Self assembly requirements for successful and complex self assembly, which evolved from the macro and micro comparison, are also established and tested. A method to assemble complex structures in the micro scale is proposed and demonstrated at the meso scale. The basic concepts of self assembly and a novel approach to complex multi layer self assembly is analyzed.

Percutaneous delivery of drugs promises many advantages over oral or intravenous administration, such as a better control of blood levels, a reduced incidence of systemic toxicity, an absence of hepatic first-pass metabolism, better patient compliance, etc. However, the dermal drug transport is limited by the unsuitable physicochemical properties of most drugs and the efficient barrier function of the skin. Thus, numerous attempts have been reported to improve topical absorption of drugs, concentrating mainly on the barrier function of the stratum corneum by use of penetration enhancers and/or skin warming. An alternative and interesting possibility for improved dermal permeability is the synthesis of derivatives or analogues with the aim of changing the physicochemical properties in favour of skin permeation, efficacy and therapeutic value. Cyclizine (I) is an anti-emetic drug primarily indicated for the prophylaxis and treatment of nausea and vomiting associated with motion sickness, post operation and Meniere's disease. It acts both on the emetic trigger zone and by damping the labyrinthine sensitivity. Pharmacologically it has anti-histaminic, antiserotonergic, local anaesthetic and vagolytic actions. It is widely used and also suitable for children from six year of age. Percutaneous absorption of (I) can, among others, avoid the "first-pass" effect and the discomfort of injection. The main objective of this study was to explore the feasibility of percutaneous absorption of (I) and its alkyl analogues via physicochemical characterization and assessment of their permeation parameters. The intent was also to establish a correlation between the physicochemical properties of these compounds and their percutaneous rate of absorption. To achieve these objectives, the study was undertaken by synthesizing the alkyl analogues and determining the physicochemical parameters relevant to skin transport. Identification and level of purity for the prepared analogues were confirmed by mass spectrometry (MS), nuclear magnetic resonance (NMR) spectrometry and infrared (IR) spectrometry. Experimental aqueous solubility (25 °c & 32 °C) and partition coefficient for each compound were determined. In vitro permeation studies were performed at pH 7.4, using Franz diffusion cells with human epidermal membranes. Diffusion experiments were conducted over a period of 24 hours maintaining a constant temperature (37 DC) by means of water bath. All samples were analysed by high pressure liquid chromatography (HPLC). Cyclizine (I) has a methyl group at N-4. Increasing the alkyl chain length on N-4 of the piperazine ring resulted' in compounds with lower melting points and higher water solubility than (I). (II) exhibited 3-fold increase in water solubility, followed by (IV) with about 2.5 fold increase. The water solubility of (III) was almost the same as that of (I). Log partition coefficients increased linearly with increasing alkyl chain length. The analogues therefore, possessed more favourable physicochemical properties to be delivered percutaneously. Indeed, the in vitro skin permeation data proved that these analogues could be delivered more easily than (I) itself. The flux of (I) was 0.132 ug/cm2/h in a saturated aqueous solution. Compound (II) resulted in a 53-fold (6.952 ug/cm2/h) increase in permeation compared to (I). (III) and (IV) resulted in a 2- and 5fold enhancement of permeation respectively. Based on the results of the study, it seems that increased aqueous solubility and low level of crystallinity play a vital role in optimizing percutaneous absorption of (I) and its alkyl analogues. But the importance of the effect of increased lipophilicity cannot be ignored. The low percutaneous• absorption of (I) might be attributed to its low aqueous solubility and increased crystallinity, as is evident from the higher melting point than the analogues. From all the permeability data using aqueous solutions, it is clear that compound (II) is the best permeant of this series and in addition it is known that this compound antagonizes the effects of histamine. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.