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Advanced drug discovery techniques have produced more lipophilic compounds. Formation of an amorphous solid dispersion of such poorly water-soluble drugs improves their solubility and dissolution. This results in greater in vivo bioavailability. Thus, it is one of the recent trends in the development of oral dosage forms. In solid dispersions, the carrier is crucial for ensuring the functionality and stability of these systems. Larch arabinogalactan FiberAid grade (AGF) is generally recognized as safe (GRAS) designated, amorphous polymer. The objective of this dissertation project was to perform a comprehensive evaluation of AGF as a carrier for amorphous solid dispersions. First, a detailed characterization of the AGF polymer was performed. A special focus on its use as a solid dispersion carrier was emphasized. The glass transition temperature and the degradation temperature of the AGF polymer were ~82 oC and ~185 oC, respectively. The AGF polymer had good hygroscopicity. Ibuprofen-AGF solid dispersions were evaluated for dissolution enhancement. Ibuprofen-Hydroxypropyl methylcellulose grade K3 (HPMCK3) solid dispersions were investigated simultaneously as a control polymer dispersion. The ibuprofen-AGF solid dispersions were amorphous at nearly 20% ibuprofen load. The dissolution of the ibuprofen from AGF solid dispersions was significantly greater than that of the neat ibuprofen. The formation of the amorphous state of ibuprofen and solution-state ibuprofen-AGF interactions were the mechanisms of the ibuprofen dissolution enhancement. At a 10% ibuprofen load, the dissolution of the AGF solid dispersion was found greater than that of the dissolution of the HPMCK3 solid dispersion. Secondly, the itraconazole-AGF solid dispersions and the ketoprofen-AGF solid dispersions were characterized and compared them with the ibuprofen-AGF solid dispersions. The comparisons were established for the miscibility and dissolution enhancement. The order of increase in dissolution was ketoprofen-AGF solid dispersions > itraconazole-AGF solid dispersions> ibuprofen-AGF solid dispersions. The same order was observed for the solid-state miscibility of these drug-AGF solid dispersions. Additionally, the solid dispersions of 9 drugs with the AGF polymer were investigated to elucidate the detailed mechanism of drug crystallization inhibition by the AGF polymer. The inherent tendency of the AGF polymer to inhibit the drug crystallization, drug-AGF solid-state hydrogen bonding and the anti-plasticizing effect of AGF were the mechanisms underlying the crystallization inhibition by the AGF polymer. Last, a storage stability of ibuprofen-AGF amorphous solid dispersions after storage under accelerated conditions (for 3 months) and ambient conditions (for 6 months) was investigated. The amorphous ibuprofen from AGF solid dispersions was physically and chemically stable under stability conditions. In summary, the AGF polymer was evaluated as a novel carrier for formation of an amorphous solid dispersions. The studies established that the AGF polymer was comparable to HPMCK3 polymer. The AGF polymer could be more advantageous than the HPMC polymer for the preparation of solid dispersion when faster dissolution is desired at lower drug load. / Pharmaceutical Sciences

Nanoparticle mediated drug delivery approaches provide potential opportunities for targeting and killing of intracellular bacteria. Among them, the porous silica nanoparticles deserve special attention due to their multifunctional properties such as high drug loading, controlled drug release and targeting of organs/cells. A review of the functional requirements of an ideal drug delivery system is provided. A general comparison between different drug delivery carriers and key issues to be addressed for intracellular drug delivery is discussed. Acid catalyzed and acid-base catalyzed, sol-gel derived, silica xerogel systems were investigated for sustained release of an aminoglycosides antimicrobial against salmonella infection in a mouse model. The release of gentamicin from the inner hollow part of the carrier is delayed. Further, the higher porosity of the acid–base catalyzed silica xerogel allows for high drug loading compared to the acid catalyzed silica xerogel system. Efficacy of these particles in killing intracellular bacteria (salmonella) was determined by administering three doses of porous silica loaded gentamicin. This proved to be useful in reducing the salmonella in the liver and spleen of infected mice. Furthermore, the presence of silanol groups provides the ability to functionalize the silica xerogel system with organic groups, poly (ethylene glycol) (PEG), to further increase the hydrophilicity of the silica xerogel matrix and to modify the drug release properties. Increase in the hydrophilicity of the matrix allows for faster drug release rate. In order to facilitate controlled drug release, magnetic porous silica xerogels were fabricated by incorporating iron particles within the porous silica. The particles were fabricated using an acid-base catalyzed sol-gel technique. The in-vitro drug release studies confirm that the release rate can be changed by the magnetic field "ON-OFF" mechanism. This novel drug release methodology combined with the property of high drug loading capacity proves to be influential in treating salmonella intracellular bacteria. The potential application of any drug delivery carrier relies on the ability to deliver the requisite drug without adversely affecting the cells over the long term. We have developed silica/calcium nanocomposites and evaluated their solubility behavior. The solubility of particles was characterized by particle size measurements for different periods of time. It was found that the solubility behaviour of the silica/calcium particles was dependent on their calcium content. The results obtained demonstrate the potential to use mesoporous silica/calcium nano-composites for drug delivery applications. The significant contribution of this research to drug delivery technology is on design and development of the novel porous core-shell silica nano-structures. This new core-shell nano-structure combines all the above mentioned properties (high drug loading, magnetic field controlled drug release, and solubility). The main aim of preparing these porous core-shell particles is to have a control over the solubility and drug release property, which is a significant phenomenon, which has not been achieved in any other drug delivery systems. The shell layer acts as a capping agent which dissolves at a controllable rate. The rate at which the shell layer dissolves depends on the composition of the particles. This shell prevents the drug "leakage" from the particles before reaching the target site. The core layer drug loading and release rate was modified by application of a magnetic field. Additionally, inclusion of the calcium ions in the core layer destabilizes the silica network and allows the particles to dissolve at an appropriate rate (which can be controlled by the concentration of the calcium ions). / Ph. D.

Amorphous solid dispersion (ASD) is a popular method to increase drug solubility and consequently poor drug bioavailability. Cellulose ω-carboxyesters were designed and synthesized specifically for ASD preparations in Edgar lab that can meet the ASD expectations such as high Tg, recrystallization prevention and pH-triggered release due to the free -COOH groups. Rifampicin (Rif), Ritonavir (Rit), Efavirenz (Efa), Etravirine (Etra) and Quercetin (Que) cellulose ester ASDs were investigated in order to increase drug solubility, prevent release at low pH and controlled release of the drug at small intestine pH that can improve drug bioavailability, decrease needed drug content and medication price to make it affordable in third world countries, and extent pill efficiency period to improve patient quality of life and adherence to the treatment schedule. The studies were compared with cellulose based commercial polymers to prove the impact of the investigation and potential for the application. Furthermore, the in vitro results obtained were further supported by in vivo studies to prove the significant increase in bioavailability and show the extended release. The need of new cellulose derivatives for ASD applications extended the research area, the design and synthesis of a new class of polymers, alkyl cellulose ω-carboxyesters for ASD formulations investigated and the efficiency of the polymers were summarized to show that they have the anticipated properties. The polymers were synthesized by the reaction of commercial cellulose alkyl ethers with benzyl ester protected, monofunctional hydrocarbon chain acid chlorides, followed by removal of protecting group using palladium hydroxide catalyzed hydrogenolysis to form the alkyl cellulose wcarboxyalkanoate. Having been tested for ASD preparation, it was proven that the polymers were efficient in maintaining the drug in amorphous solid state, release the drug at neutral pH and prevent the recrystallization for hours, as predicted. / Ph. D.

Hot-melt extruded solid dispersion technique is increasingly employed to improve the solubility of poorly water-soluble drugs. The technique relies on the enhanced solubility of the amorphous form of the drug compared to its crystalline counterpart. These systems however are thermodynamically unstable. This means that the drug crystallises with time. Therefore, efforts to measure the stability of these systems over the life span of the product are crucial. This study focused on investigating the use of Hansen Solubility Parameters to quantify polymer-drug interaction and to predict the stability of solid dispersions. This was achieved through a systematic review of hot-melt extruded solid dispersion literature. The study also investigated the use of a combined mechanical and rheological model to characterise the physicochemical and release behaviour of three solid dispersion immediately after preparation and after storage for one month at 40oC or three months at room temperature. Results revealed that the total solubility parameter |ΔбT| was able to predict the stability of the systems for more than 4 months using a cut-off point of 3 MPa-1 with a negative predictive value of 0.9. This was followed by ΔбD with a cut-off point of 1.5 MPa- 1. Moreover, Dynamic Mechanical Analyser and shear rheometry data were shown to be more sensitive than Differential Scanning Calorimetry, Powder X-Ray Diffraction, Scanning Electron Microscope and Fourier Transform Infrared in detecting crystallisation and the interaction between the drug and the polymer. The Dynamic Mechanical Analyser data were consistent with the dissolution behaviour of the samples when comparing the freshly prepared samples with those after storage. The results highlight the need for a unified characterisation approach and the necessity of verifying the homogeneity of mixing during the extrusion process.

In this experiment, more than one hundred volatile organic compounds were analyzed with the gas chromatograph. Six capillary columns ZB wax plus, ZB 35, TR1MS, TR5, TG5MS and TG1301MS with different polarities have been used for separation of compounds and illicit drugs. The Abraham solvation model has five solute descriptors. The solute descriptors are E, S, A, B, L (or V). Based on the six stationary phases, six equations were constructed as a training set for each of the six columns. The six equations served to calculate the solute descriptors for a set of illicit drugs. Drugs studied are nicotine (S= 0.870, A= 0.000, B= 1.073), oxycodone(S= 2.564. A= 0.286, B= 1.706), methamphetamine (S= 0.297, A= 1.570, B= 1.009), heroin (S=2.224, A= 0.000, B= 2.136) and ketamine (S= 1.005, A= 0.000, B= 1.126). The solute property of Abraham solvation model is represented as a logarithm of retention time, thus the logarithm of experimental and calculated retention times is compared.

Solubility prediction usually refers to prediction of the intrinsic aqueous solubility, which is the concentration of an unionised molecule in a saturated aqueous solution at thermodynamic equilibrium at a given temperature. Solubility is determined by structural and energetic components emanating from solid-phase structure and packing interactions, solute–solvent interactions, and structural reorganisation in solution. An overview of the most commonly used methods for solubility prediction is given in Chapter 1. In this thesis, we investigate various approaches to solubility prediction and solvation model development, based on informatics and incorporation of empirical and experimental data. These are of a knowledge-based nature, and specifically incorporate information from the Cambridge Structural Database (CSD). A common problem for solubility prediction is the computational cost associated with accurate models. This issue is usually addressed by use of machine learning and regression models, such as the General Solubility Equation (GSE). These types of models are investigated and discussed in Chapter 3, where we evaluate the reliability of the GSE for a set of structures covering a large area of chemical space. We find that molecular descriptors relating to specific atom or functional group counts in the solute molecule almost always appear in improved regression models. In accordance with the findings of Chapter 3, in Chapter 4 we investigate whether radial distribution functions (RDFs) calculated for atoms (defined according to their immediate chemical environment) with water from organic hydrate crystal structures may give a good indication of interactions applicable to the solution phase, and justify this by comparison of our own RDFs to neutron diffraction data for water and ice. We then apply our RDFs to the theory of the Reference Interaction Site Model (RISM) in Chapter 5, and produce novel models for the calculation of Hydration Free Energies (HFEs).

The goal of the thesis is to create a predictor of the effect of a mutation on protein solubility given its initial 3D structure. Protein solubility prediction is a bioinformatics problem which is still considered unsolved. Especially a prediction using a 3D structure has not gained much attention yet. A relevant knowledge about proteins, protein solubility and existing predictors is included in the text. The principle of the designed predictor is inspired by the Surface Patches article and therefore it also aims to validate the results achieved by its authors. The designed tool uses changes of positive regions of the electric potential above the protein's surface to make a prediction. The tool has been successfully implemented and series of computationally expensive experiments have been performed. It was shown that the electric potential, hence the predictor itself too, can be successfully used just for a limited set of proteins. On top of that, the method used in the article correlates with a much simpler variable - the protein's net charge.

Uganda is well endowed with economic quantities of mineral salts present in the interstitial brines and evaporite deposits of Lake Katwe, a closed (endorheic) saline lake located in the western branch of the great East African rift valley. Currently, rudimentally and artisanal methods continue to be used for salt extraction from the lake raw materials. These have proved to be risky and unsustainable to the salt miners and the environment and they have a low productivity and poor product quality. This work involves the investigation of the salt raw materials that naturally occur in the brines and evaporites of Lake Katwe. The purpose is to propose strategies for the extraction of improved salt products for the domestic and commercial industry in Uganda. The literature concerning the occurrence of salt and the most common available technologies for salt extraction was documented. Also, field investigations were undertaken to characterize the salt lake deposits and to assess the salt processing methods and practices. The mineral salt raw materials (brines and evaporites) were characterized to assess their quality in terms of the physical, chemical, mineralogical, and morphological composition through field and laboratory analyses. An evaluation of the potential of future sustainable salt extraction from the lake deposits was done through field, experimental, and modeling methods. Moreover, the mineral solubilities in the lake brine systems and dissolution kinetics aspects were investigated. The results reveal that the salt lake raw materials contain substantial amounts of salt, which can be commercialized to enable an optimum production. The brines are highly alkaline and rich in Na+, K+, Cl-, SO42-, CO32-, and HCO3-. Moreover, they contain trace amounts of Mg2+, Ca2+, Br-, and F-. The lake is hydro-chemically of a carbonate type with the brines showing an intermediate transition between Na-Cl and Na-HCO3 water types. Also, the evaporation-crystallization is the main mechanism controlling the lake brine chemistry. These evaporites are composed of halite mixed with other salts such as hanksite, burkeite, trona etc, but with a composition that varies considerably within the same grades. The laboratory isothermal extraction experiments indicate that various types of economic salts such as thenardite, anhydrite, mirabilite, burkeite, hanksite, gypsum, trona, halite, nahcolite, soda ash, and thermonatrite exist in the brine of Lake Katwe. In addition, the salts were found to crystallize in the following the sequence: sulfates, chlorides, and carbonates. A combination of results from the Pitzer’s ion-interaction model in PHREEQC and experimental data provided a valuable insight into the thermodynamic conditions of the brine and the sequence of salt precipitation during an isothermal evaporation. A good agreement between the theoretical and experimental results of the mineral solubilities in the lake brine systems was observed with an average deviation ranging between 8-28%. The understanding of the mineral solubility and sequence of salt precipitation from the brine helps to control its evolution during concentration. Hence, it will lead to an improved operating design scheme of the current extraction processes. The dissolution rate of the salt raw materials was found to increase with an increased temperature, agitation speed and to decrease with an increased particle size and solid-to-liquid ratio. Moreover, the Avrami model provided the best agreement with the obtained experimental data (R2 = 0.9127-0.9731). In addition, the dissolution process was found to be controlled by a diffusion mechanism, with an activation energy of 33.3 kJ/mol. Under natural field conditions, the evaporative-crystallization process at Lake Katwe is influenced by in-situ weather conditions. Especially, the depth of the brine layer in the salt pans and the temperature play a significant role on the brine evaporation rates. With the optimal use of solar energy, it was established that the brine evaporation flux can be speeded up in the salt pans, which could increase the production rates. Moreover, recrystallization can be a viable technique to improve the salt product purity. Overall, it is believed that the current work provides useful information on how to exploit the mineral salts from the salt lake resources in the future. / <p>QC 20151217</p>

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