Rozprawy doktorskie na temat „Solubility”

La cristallisation est un procédé majeur de l’industrie pharmaceutique. Dans la mise au point d’un nouveau procédé de cristallisation, l’information essentielle est la solubilité de la molécule produite dans le solvant de cristallisation. Cette donnée n’est généralement pas connue lors de la phase de développement d’un nouveau principe actif. Elle doit donc être déterminée. L’objectif de cette thèse est d’étudier, et d’approfondir, l’utilisation de modèles thermodynamiques pour prédire la solubilité de molécules organiques complexes. Pour cela, six molécules sont prises pour référence : l’ibuprofène, le paracétamol, les acides salicylique, benzoïque et 4-aminobenzoïque et l’anthracène. Les modèles étudiés sont UNIFAC et ses modifications, COSMO-SAC, NRTL-SAC et PC-SAFT. Dans un premier temps, les potentialités de chaque modèle pour prédire la solubilité dans des solvants purs et des mélanges de solvants sont analysées. Dans un second temps, le modèle COSMO-SAC est approfondi et amélioré pour la prédiction des équilibres liquide-solide mettant en jeu des molécules complexes. Enfin, une nouvelle voie de mesure expérimentale de la solubilité dans de très faibles volumes est ouverte par l’intermédiaire de l’outil microfluidique.

The solubilities of benzene, naphthalene and anthracene were measured in five binary solvent systems. These systems consised of water and one of the following water miscible organic solvents: acetone, acetonitrile, methanol, ethanol, and isopropanol. The measurements were made at intervals of 0.1 volume fractions of the organic cosolvent. Solubility data were also collected for the above solutes in mixed cosolvents. solvent systems containing three In addition, the solubilities of and six five other aromatic solutes were measured in the binary solvent systems of methanol/water and acetone/water. The data was used to test the log-linear solubility model of Yalkowsky (1981). The model predicts a linear relationship between the solubility of a solute in a binary solvent system (S(m)) and the volume fraction of cosolvent present (f(c)) log S(m) = σf(c) + log S(w) Where S(w) is the solubility of the solute in water and σ is the proportionality constant and slope of the curve. The model is easily extended to multiple mixed solvents by combining the σ values from the binary solvent systems. log (S(m)/S(w)) = Σ₁ (σ₁£₁) A method was developed to estimate σ in a given binary solvent system from the octanol-water partition coefficient of the solute. Combining this method with the generalized solubility equation of Yalkowsky to estimate S(w), allows a priori estimates of solubility in mixed solvents. Maximum deviations in the binary solvent systems studied were related to maxima in excess density. In the alcoholic binary solvent systems the minima were related to minima in the heats of mixing of the two cosolvents. The herbicide atrazine deviated dramatically from the model. The system was examined for possible changes in the crystal structure of atrazine. It was found that some crystal modification occured in the presence of mixed solvents. The rate of the change appears to be dependant on the concentration of the cosolvent. A change or modification in the crystal violates one of the basic assumptions of the log-linear model. The assumption is that the crystal contributes equally to the solubility behavior irrespective of the solvent system. It was determined that atrazine undergoes a polymorphic transition in the systems studied. It is postulated that this polymorphism is responsible for the anomolous solubility behavior observed for atrazine.

Solubility is the amount of solute in the solvent system at phase equilibrium with certain temperature and pressure. Many of the new chemical entities are lipophilic molecules that require techniques to enhance solubility. Solubility enhancement can be achieved by either physical and/or chemical modification of the drug. Various techniques are available for solubility enhancement of poorly soluble drugs include particle size reduction, salt formation, solid dispersions, use of surfactants, prodrug, crystal modification, etc. In this study, the three model drugs belong to BCS class II and IV having low solubility with a certain range of physicochemical properties were studies in solubility enhancement using fusion method, co-precipitation, nano-milling and spray drying techniques. The two different polymers employed for solubility enhancement are PEG 8000 and PVP 40,000. Solubility was determined by Shake Flask method at the temperature of 37±0.1 °C. The objective is to investigate the enhancement of solubility of the three model drugs namely Glipizide, Carvedilol and Furosemide in 1:1, 1:5 and 1:10 drug-polymer ratios and are characterized by Differential Scanning Calorimetry (DSC). The Solubility of Glipizide was enhanced from 11.18 ± 1.78 µg/ml to 35.73 ± 0.04 µg/ml by 219 % increase with nano-milling technique at 1:5 ratio with PEG 8000 as carrier whereas with PVP 40000 as carrier, 286 % increase in solubility to 43.26 ± 7.87 µg/ml was observed at 1:1 ratio by fusion method. The solubility of Carvedilol was enhanced from 5.04 ± 0.55 µg/ml to 17.51 ± 0.94 µg/ml by 246 % at 1:5 ratio by fusion method with PEG8000 as carrier and 2924 % enhancement in solubility to 152.70 ± 9.09 µg/ml at 1:10 ratio by nano-milling with PVP40000 as the carrier. Furosemide showed an increase in solubility from 55.94 ± 2.48 µg/ml to 164.11 ± 9.18 µg/ml by 193 % at 1:10 ratio by nano-milling technique with PEG8000 as carrier whereas with PVP40000 as carrier, 444 % increase was observed at 1:1 ratio by nano-milling technique with solubility of 304.52 ± 23.11 µg/ml. The data showed that the decrease in percentage crystallinity and enthalpy of fusion of the model drugs upon implementing solubility enhancement techniques with the effect of particle size and the carrier used resulted in the increase of aqueous solubility of the model drugs.

The medium offering the greatest resistance to heat transfer from the freeze-drying shelf to the moving and subliming surface is the space between the flat shelf top and the concave vial bottom. The resistance to heat transfer can be greatly reduced by improving the thermal conductivity of the intervening space. Several heat transfer augmentation devices, including a multilayered corrugated aluminum quilt and a conformable fluid cushion device, which fill this gap are described. The devices are inexpensive and easy to use. Experimental data show that the resistance of the intervening space is reduced appreciably and the drying rate is greatly increased. The fluid cushion device is superior to the aluminum quilt as it reduces the consequences of spillage of solution and provides greater intervial uniformity among the same batch of vials. Drying times obtained in experiments with and without the fluid cushion device are compared here for different sizes and different types of vials. Product evaluation is conducted by measuring the reconstitution time and observing the product under a microscope. The solubilities of two univalent electrolytes, sodium chloride and potassium chloride, have been measured in eight cosolvent-water binary systems. The solubility of both the solutes has been found to be adequately described by the log-linear solubility equation, log S(m) = log S(w) + fσ. The rank order of the desolubilization slopes obtained for the electrolyte solutes is compared with the solubilization of nonelectrolyte solutes. These results indicate that a cosolvent which is most effective in solubilizing a nonelectrolyte is also most effective in desolubilizing an electrolyte. The solubility of oxacillin sodium in methanol-water mixtures has been determined at various temperatures ranging from +21 to -26 degrees centigrade. The data has been fitted to the log-linear relationship as proposed by Yalkowsky et. al. The heat of solution is determined using the van't Hoff equation and was found to be nearly constant at 1.2 Kcal/mole. There appears to be no dependency of the slope of the log S(m) vs. fraction cosolvent plot to the temperature. The data suggests that there is a polymorphic or amorphic transition of oxacillin at -14.5 degrees centigrade.

Methods of determining the aqueous solubilities of twelve chlorinated benzenes were evaluated in pure and in different water matrices. In pure water, results were comparable with the calculated values. Higher chlorinated tetrachlorobenzenes (TeCBs), pentachlorobenzenes (PCBz), and hexachlorobenzenes (HCBs) gave better precision and accuracy than lower chlorinated monochlorobenzenes (MCBs), dichlorobenzenes (DCBs), or trichlorobenzenes (TCBs).

Solubility of gas or vapor components in glassy polymers is relevant in numerous processes and applications, such as the development of gas separation membranes or gas barrier materials for packaging, analysis of gas sensors, piping of gaseous streams and many more. Modeling tools for the prediction of gas solubility in glassy polymers would be indeed of great help to the evaluation of performances of different materials in above mentioned applications. It would allow for a much more efficient selection procedure with respect to the direct experimental analysis which, in turn, would be not attainable at all for the case of complex gaseous mixture with variable temperature, pressure and gas composition. In fact, different from the case of rubbery polymers, glassy polymers are not at equilibrium state and effect of above process parameters are much more complex and highly non-linear. A thermodynamically consistent approach (NET-GP) was introduced around twenty years ago [Doghieri, F; Sarti, GC (1996) “Nonequilibrium lattice fluids: A predictive model for the solubility in glassy polymers” MACROMOLECULES, vol.29 (24), pag.7885-7896] to extend the application of standard equilibrium thermodynamic expression for free energy and chemical potential of polymer/solute systems below the glass transition temperature. The approach proved to be successful in the representation of effect of temperature, pressure and gas composition in glassy polymers, provided the equilibrium volumetric behavior of the latter is known, together with mass density in actual non-equilibrium conditions. For each polymeric species, experimental data for two distinct gaseous species in a relatively wide pressure range will be selected to retrieve model parameters for the given polymer. The model procedure will be then used to attempt for the prediction of gas solubility for all other gases of interest, at different pressure, for the same polymeric species.

The prepared polyelectrolyte complexes of anionic copolymer of divinyl ester and maleic anhydride and cationic water soluble chitosan proved to be able to undergo reversible phase transition, in particular at physiological pH and ionic strength. Formation of either soluble or insoluble complexes occurred depending on pH value, charge ratio and degree of polymerization of the polymers. The stability of positively or negatively charged complexes against destruction action of the added salt drastically increased in acidic media presumably owing to H-bonds formation. According to light-scattering data, the size of the soluble complexes varied from 100 to 300 nm and remained virtually unchanged under storage after lyophilizing drying and resuspending in the same medium. When you are citing the document, use the following link http://essuir.sumdu.edu.ua/handle/123456789/35468

Aqueous solubility is one of the most important physical properties to consider in drug discovery and development. Drug candidates with poor solubility often have poor bioavailability, which leads to increased developmental cost and efforts. Therefore, there is a strong trend to perform solubility screening of drug candidates as early as possible in the drug discovery and development process. While experimental methods are being developed to increase the throughput of solubility measurement, the development of aqueous solubility prediction methods can be a powerful complementary tool. This dissertation starts by compiling a large collection of aqueous solubility data for organic compounds covering diverse classes of structures. The data set is first used to critically evaluate the General Solubility Equation (Yalkowsky et al., 1980, 1999), one of the most widely used methods for aqueous solubility prediction. The General Solubility Equation performs very well overall as measured by the average absolute error (AAE) of 0.56 log unit. Detailed analyses indicate that it gives better predictions for non-electrolytes than some classes of weak electrolytes. This method is then compared with a method based on an amended solvation energy relationship, which considers the hydrogen bonding potentials of functional groups. It is shown that averaging the prediction results from the two methods gives better prediction than either method alone. Following the concept of the AQUAFAC model developed by Myrdal et al. (1992, 1993, 1995), an extended version of the original structural fragmentation scheme is developed. The model is trained on the data set and has an R2 value of 0.881 and a standard error of estimation of 0.819 log unit. Group contribution parameters for a set of 104 fragments are obtained. A new group contribution model is developed to suit the needs in the early drug discovery stage, when melting information is generally not available. Calculated octanol-water partition coefficient is included in the model. The model has a standard error of estimation of 0.814 log unit. When evaluated on independent test sets, the new model provides comparable prediction results with the other two models. The independence of the new model of experimental melting information makes it a suitable tool for aqueous solubility screening in early drug discovery.

Several methods have been proposed for the prediction of aqueous solubility. This study proposes the SCRATCH model for the aqueous solubility estimation of a compound directly from its structure. The algorithm utilizes predicted melting points and predicted aqueous activity coefficients for the solubility estimation, reflecting the truly predictive nature of the model. It uses two additive, constitutive molecular descriptors (enthalpy of melting and aqueous activity coefficient) and two non-additive molecular descriptors (symmetry and flexibility). The melting point prediction is trained on over 2200 compounds whereas the aqueous activity coefficient is trained on about 1640 compounds, making the model very rigorous and robust. The model is validated using a 10-fold cross- validation.A comparison with the General Solubility Equation suggests that the SCRATCH predicted aqueous solubilities have a slightly more average absolute error. This could result due to the fact that SCRATCH uses two predicted parameters whereas the GSE utilizes only one predicted property. Although the GSE is simpler to use, the drawback of requiring an experimental melting point is overcome in SCRATCH which can predict the aqueous solubility of a compound just based on its structure and no experimental values.

When considering oral administration, drug release from its pharmaceutical form and its dissolution into gastrointestinal fluids generally precedes absorption and systemic availability. The solubility-dissolution behaviour of a drug is frequently the rate-limiting step to absorption of drugs from the gastrointestinal tract (BCS class II drugs). Poor aqueous solubility has always been a very challenging obstacle as it is, together with membrane permeability, an essential factor in the limitation of a drug’s bioavailability following oral administration. Since an increasing number of newly developed drug candidates in pre-clinical development phases present poor water-solubility characteristics, there is a great need for formulation approaches to overcome this factor.

Out of the many ways to increase a product’s solubility/dissolution rate characteristics with the aim of enhancing its oral bioavailability, drug formulation as nanoparticles has received much-increased interest over the last decade. The hypothesis behind dissolution rate enhancement, considering drug particle size reduction to nanometer range, lies primarily in a much-increased effective surface area (Noyes-Whitney) presented by the resulting drug nanoparticles. Out of the various technologies available for drug particle size reduction to nanometer range, milling using high pressure homogenization is regarded as one of the simplest and most effective techniques. High pressure homogenization is a solvent-free process and is relatively rapid (time-saving). Furthermore, and most importantly, the scaling up of this technique is already established; processing capacities ranging from 3 l/h (e.g. EmulsiFlex C3®: minimum sample volume - 10 ml) to 1000 l/h (e.g. EmulsiFlex C1000®: minimum sample volume - 2 l).

Four model drugs were studied in this work. Nifedipine (NIF), an extensively studied poorly water-soluble drug in the literature, was used as the main model on which most of the development was done. In parallel to the work carried out on NIF, three UCB S.A. molecules currently under development were also studied as poorly water-soluble drugs: these being ucb-35440-3, UCB-A and UCB-B (salt of UCB-A). These three UCB S.A. model drugs are, contrarily to NIF, predicted highly dosed drugs and are weak bases, and thus present pH-dependent solubility profiles, which allowed us to investigate model drugs with different profiles.

Firstly, investigations regarding appropriate formulation development (stabilizer (surfactant) selection) and appropriate high pressure homogenization operating conditions (pre-milling cycles, influence of the number of high pressure homogenizing cycles, influence of homogenizing pressure, influence of sample temperature) were made. It has been shown, through this development, for the four studied model drugs, that high pressure homogenization is an appropriate technique for reducing drug particle size to nanometer range (NIF &61566; 290 nm, ucb-35440-3 &61566; 180 nm, UCB-A &61566; 350 nm and UCB-B &61566; 250 nm). Investigations regarding water-removal from the nanosuspensions obtained and most importantly regarding the redispersion characteristics of the retrieved powders (i.e. nanoparticles) were then carried out. In that regard, it has been shown that the presence of carriers in the formulation is essential for limiting nanoparticles agglomeration during the water-removal operation.

Drug crystalline state characterizations before and following particle size reduction were then carried out on the three studied model drugs, mainly through DSC and PXRD studies. In fact, one of the advantages of this particle size reduction approach (using high pressure homogenization), versus other frequently studied solubility/dissolution rate enhancement technologies (e.g. such as solid dispersions), is that original crystalline state shall not be altered in such a way that the achieved increased solubility and dissolution rate characteristics do not rely on the presence of the amorphous form of the drug; this furthermore implying a greater time-stability of the developed formulations. Through the data obtained, it has been shown that original drug crystalline state seems to be unaltered following particle size reduction.

In vitro solubility and dissolution characteristics were then evaluated on the formulations developed in order to verify the posed hypothesis regarding effective surface area increase. It has been shown through these studies that drug solubility and most importantly drug dissolution rate can be significantly enhanced for nanoparticulate systems (verified for NIF, ucb-35440-3, UCB-A and UCB-B). For example, solubility was enhanced from 26 µg/ml vs. 19.5 µg/ml for NIF nanoparticles and the dissolution characteristics showed that 100% of the tested dose (equivalent to 10 mg NIF) was already dissolved following 10 min vs. less than 5% for un-milled NIF. Following these very interesting and promising results, and preliminary to the in vivo pharmacokinetic studies carried out, in vitro permeation studies (apical to basolateral transfer studies) across intestinal cell models (Caco-2 and HT29-5M21 cultures and co-cultures) were carried out. This evaluation was only carried out using NIF as a model drug and showed a 6-fold increase in the permeation rate for NIF nanoparticles. The influence of chitosan (permeability enhancer/bioadhesive polymer) in the NIF nanoparticle formulation with regard to in vitro NIF permeation rate was also evaluated.

In vivo pharmacokinetic studies in rats were conducted using NIF and ucb-35440-3 as model drugs. The very different profiles of these two model drugs allowed us to retrieve interesting information regarding the in vivo behaviour of the developed formulations. As expected from the in vitro (i.e. solubility/dissolution/permeation) studies and results obtained for NIF, an increased extent of exposure could be observed for NIF nanoparticles versus un-milled NIF; the difference being more pronounced when the formulations were orally administered into capsules (2.5-fold increase in extent of exposure and 6-fold increase in Cmax). For ucb-35440-3, a poorly water-soluble weak base with a reported significant food effect considering oral bioavailability, an increased extent of exposure for nanoparticles, versus the un-milled drug, could only be observed in fasted state (4-fold increase in extent of exposure and 2.7-fold increase in Cmax). These different, diet-relative observations allowed us to put forward some limitations and precautions (considering poorly water-soluble weak bases) relative to the possibility of drug reprecipitation following stomach’s exiting, particularly if dissolution in the stomach is quite fast (e.g. nanoparticulate systems).

In parallel to the in vivo pharmacokinetic evaluation of NIF nanoparticles, evaluation of the antihypertensive effect of the systems developed following oral administration, using spontaneously hypertensive rats, was also carried out and compared to un-millled NIF. The results obtained showed a significant drop in systolic blood pressure for NIF nanoparticles (32% reduction of initial SBP following 30 min vs. 1% for un-milled NIF) and nicely complemented the in vitro and in vivo results obtained for NIF nanoparticles.

Finally, a stability study of the optimized NIF nanoparticle formulation was carried out with respect to reported ICH conditions (25°C/60% RH; 30°C/65% RH; 40°C/75% RH). The results showed that the studied NIF nanoparticle formulation retains all its original characteristics (dissolution, crystalline state, redispersion characteristics); this being verified over time (12 months) and for each of the three storage conditions studied.

Doctorat en sciences pharmaceutiques
info:eu-repo/semantics/nonPublished

The relationship between aqueous activity coefficients (log γ(w)) and different physico-chemical properties has been studied for a number of solutes by both empirical correlations as well as by applying existing theoretical models. The solute properties selected have been classified into three categories: geometrical, polar, and electrostatic. The solutes chosen were divided into two major groups: (a) Training Set. Structurally simple compounds, i.e., each containing only one functional group, and (b) Test Set. A series of drugs and pollutants covering a wide variety of functional groups. The Training Set is in turn formed by four sub-sets of structurally related solutes, each representative of typical data sets used in the literature for solubility studies. Linear relationships were found for polar and geometric parameters in agreement with those reported in the literature. However, although the overall correlations are good, the quality of the regressions among the sub-sets is not uniform. The generality of the relationships obtained with the Training Set was tested by applying the obtained expressions to estimate log γ(w) of the solutes of the Test Set. It was found that the parameters of the theoretical models are the only ones whose relationship with log γ(w) is maintained for both the Training and the Test sets. The theoretical models used are: octanol-water partition coefficient estimated by both Rekker's (parameter LOGP) and by Leo's (parameter PCLOGP) methods; the solubility group contributions method of Wakita et al. (1986) (parameter WAKITA); the Linear Solvation Energy Relationships model (parameter KAMLET), and the UNIFAC model. The theoretical approaches were evaluated based on two criteria: accuracy of predictions and range of applicability. The accuracy of predictions was quantitated by a prediction coefficient, P², which although analogous to regression coefficient (R²) is far less flexible. Prediction coefficient is sensitive not only to scatter of the predictions but also to the systematic errors of the model being tested. The range of applicability was quantitated by the fraction (f) of solutes within the data set for which estimates by the given methodology are possible. The Accuracy-Generality Product (AGP) defined as the product of P² and f was used as the overall criterion for evaluation. The results indicated that the quality of predictions of the theoretical models as determined by the AGP is PCLOGP > LOGP > WAKITA > UNIFAC > KAMLET, for both the Training and Test sets.

Apatites are a diverse class of phosphate minerals that are important in a great variety of natural and industrial processes. They are, for example, used as raw material in fertiliser production and in the remediation of metal-contaminated soils. Hydroxyapatite Ca5(PO4)3OH, (HAP) and fluorapatite Ca5(PO4)3F, (FAP) are similar to the biological apatite that is the main constituent of mammalian bone and teeth, and they are therefore promising materials for artificial bone and tooth implants. This thesis is a summary of four papers with focus on dissolution and surface complexation reactions of HAP and FAP in the absence and presence of both organic ligands and the natural and commonly occurring iron oxide goethite (α-FeOOH). The dissolution and surface complexation of HAP and FAP was investigated with a combination of different techniques. Potentiometric acid/base titrations and batch experiments were combined with X-ray Photoelectron Spectroscopy (XPS) and Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) Spectroscopy to generate dissolution and surface complexation models for both apatites. The results from these studies showed that both apatites form surface layers that are different from their bulk compositions when equilibrated in aqueous solutions. The modeling efforts predicted speciation of these surfaces as well as the concentration of the dissolution products in the solution. The interaction between organic ligands and the apatite surfaces was also investigated and the results from this study show that the organic ligands form outer-sphere complexes on the apatite surfaces over a large pH interval, and that this adsorption enhances the dissolution of apatites. The presence of goethite also enhances the dissolution of FAP as it acts as a sink for the phosphate released from FAP. Phase transformation in this system was detected using ATR-FTIR as the phosphate adsorbed to the goethite surface precipitates as FePO4 (s) after approximately 15 days of reaction time. This changes the speciation, and possibly also the bioavailability of phosphate in this two-mineral system.

The solubilities of four saturated, mono-acid triglycerides: Trilaurin, Trimyristin, Tripalmitin and Tristearin have been determined in supercritical Carbon Dioxide, at 35, 40, 47 and 55°C and at CO2 densities of 0.57, 0.66, 0.73, 0.78, 0.84 and 0.89 g.cm-3. These solubilities were reproducible to within 10% and agreed well with those of a previous worker, in the mid-to-high density range. The experimental data were correlated using several theoretical and empirical methods. Of the empirical methods, regression of the triglyceride solubility data against a linear function of temperature and density was found to give the least mean square deviation. When a suitable functional form was used for the binary interaction parameter, the Carnahan Starling modification to the van der Waals equation of state was the most satisfactory theoretical correlation tested. A new experimental apparatus to determine solubilities in supercritical fluids was designed and constructed. The design featured the particular advantage that a microsampling technique using direct coupling to an HPLC apparatus was used to take samples of the high pressure saturated CO2 stream. This obviated problems due to depressurisation of the outlet stream. Carbon dioxide was chosen to be the solvent for its low critical properties, low toxicity and ready availability. The triglycerides were selected as solutes for their relevance to the Dairy and Food Industries. During the course of this work literature references to solubility data since 1982 were compiled.

The solubility of diuron was determined in binary and ternary cosolvent-water systems. The binary systems were composed of a completely miscible organic solvent (CMOS) and water while the ternary systems incorporate partially miscible organic solvents (PMOS) into the binary systems. Due to the low aqueous solubilities of trichloroethylene and toluene, the PMOS's do not behave as cosolvents and they do not play an important role in altering solubility.

Solubility of drugs in non-aqueous systems is very important in understanding the partitioning and transport behavior. The present study was undertaken to evaluate the entropic and enthalpic contribution to activity coefficient of organic compounds (polycyclic aromatic hydrocarbons, aliphatic acids, aliphatic alcohols etc.) in non-aqueous solvents. The activity coefficient can be written as: ln γ₁ = ln γ₁ᶜ + ln γ₁ʳ where superscript "c" and "r" denote entropic (combinatorial) and enthalpic contribution respectively. We selected three solvent systems: benzene, triolein and octanol. The different models considered in this study were Flory-Huggins, Scatchard-Hildebrand, UNIQUAC combinatorial and UNIFAC residual. A combination of Flory-Huggins and Scatchard-Hildebrand which accounts for both the entropic and enthalpic effects gives the best predictions in all the solvents considered.

The phase-out of chlorofluorocarbons (CFCs) has resulted in an expanding new area of research in alternative ozone friendly propellants, for example hydrofluoroalkanes (HFAs). The HFA solvent system is unique in that many CFC soluble compounds behave differently in the HFA alternatives, such as HFA-134a and HFA-227. The reason for the difference in solubility is not fully recognized. This work investigates the solubility of 22 compounds in HFA-227 with the addition of ethanol as a cosolvent. The physical properties of both solute and solvent were investigated in order to determine the effects on solubility. The solubilities of 5 compounds in HFA-134a were also investigated. A thermodynamic approach was utilized in order to look at the enthalpic and entropic effects on solubility in the propellant. Due to the high vapor pressure of propellants, a liquid model was utilized, owing to its ease of use in characterizing solubility. The correlation between the liquid model 2H,3H-decafluoropentane (DFP) and the propellants HFA-134a and HFA-227 was examined.The solubilities in HFA-227 with ethanol ranged from 0.001 to 3.282 %w/w, where the solubilities always increase when ethanol was added. The experimental solubilities were compared to calculated values obtained from ideal solubility and regular solution theory models. A clear correlation with the ideal solubility (melting point) combined with an intercept term and two physical properties was noted. A regression approach was also used to predict the activity coefficient in HFA-227 with 0 - 20% ethanol. These equations were combined with the extended ideal solubility equation, creating a useful predictive equation with AAE values ranging from 0.32 to 0.36, or factor errors of 2.09 to 2.29. The equations shown in this work are useful for the prediction of solute solubility in HFA-227/ethanol mixtures.Results in the liquid model DFP with 0 - 20% ethanol show that a regression equation results in a useful predictive equation for the solubilities in both HFA-134/ethanol and HFA-227/ethanol systems, where the AAE values ranged from 0.3 to 0.56, or factor errors of 2.0 to 3.6.The solubilities of a series of chlorobenzene compounds along with a group of hydrogen donating and/or accepting compounds was examined in HFA-134a. The entropic effects appear to be the limiting factor in the solubility of these compounds. The compounds capable of hydrogen accepting and donating exhibited negative enthalpy of mixing values when placed in HFA-134a, a stark contrast to the values obtained for the chlorobenzenes. This suggests HFA-134a is able to strongly interact with solutes capable of donating or accepting hydrogen.

The solubility of anthracene was measured in binary and ternary co-solvent-water systems. The binary systems consisted of water and a completely miscible organic solvent (CMOS); while the ternary system incorporated a partially miscible organic solvent (PMOS) into the binary systems. The data were used to test the following model:(UNFORMATTED TABLE OR EQUATION FOLLOWS) log Sᵃ(c,p,w) = log Sᵃ(w) + f(c) σᵃ(c) + [(Sᴾ(w) 10 (f(c) σᴾ(c))/D(p)] σᵃ(p). (TABLE/EQUATION ENDS) The terms on the right of the equality sign are the aqueous solubility of anthracene, the solubility of anthracene in CMOS-water, and the solubility of anthracene due to the incorporation of the PMOS, respectively. This model predicts that the incorporation of a PMOS, as a solubilized solute, in CMOS-water mixtures can lead to an increase in the solubility of anthracene due to the cosolvency effect of the PMOS. The results indicate a good correlation between the observed vs. predicted increase in solubility. The deviations observed may be explained by the interactions between the solvent components.

The AQUAFAC (Aqueous Functional Group Activity Coefficients) method for predicting aqueous activity coefficients proposed by Myrdal et al. (1992) is expanded to include for hydrogen bonding groups: hydroxy, carboxy, nitro and amino. Activity coefficients can be used to estimate aqueous solubility. Using aqueous solubility data, from a number of sources, for a set of subsituted aromatic compounds, group or q values are derived. Group values have been generated for a number of substituents, none have included hydrogen bonding groups (Myrdal et al., 1992,1993). Q values are related to activity coefficients through the following relationship: log gammaw = Sigmaniqi where log gammaw is the log of the activity coefficient, qi is the group value subtituent i and ni is the group frequency. Ortho effects between hydrogen bonding groups is also examined. Intramoleculat hydrogen bonding involving carboxy substituted compounds, in this research, does appear to affect aqueous solubility.

The effect of triacetin in combination with common cosolvents on the solubility of phenytoin and diazepam was studied. The cosolvents were PEG 400 and propylene glycol. In addition, the data were used to test the following model: UNFORMATTED EQUATION FOLLOWS: log Sᵈ(c,p,w) = log Sᵈ(w) + f(c)σᵈ(c) + [Sᵖ(w)10(f(c)σᵖ(c))/D(p)] σᵈ(p). UNFORMATTED EQUATION ENDS. The term on the left side of the equation is the solubility of a drug in the ternary system. This is related to the aqueous solubility of the drug, the solubility of the drug in a completely miscible organic solvent (CMOS), and the solubility of the partially miscible organic solvent (PMOS). This model was proposed by Gupta et al. (1989) and predicts the solubility of a ternary system composed of a CMOS and PMOS. The results indicate the triacetin does increase the solubility of the two poorly water-soluble drugs. There is good correlation between the observed and predicted increase in the solubility of the drugs.

The aim of the present work was to contribute to establish robust and high throughput methodology of interest in the "Drug Discovery" step commonly done in pharmaceutical laboratories. This purpose involves the exploration of the possibilities of the potentiometric Sirius methodology to determine both acidity constants and solubilities of drugs and other bioactive compounds and also to do a study about how to improve bioavailability of a model drug, Amphotericine 8, by increasing its dissolution rate. In the first part of this project, the acidic dissociation enthalpies and constants of anilinium, protonated tris (hydroxymethyl)- aminomethane (HTris+), benzoic and acetic acids, have been determined at several temperatures in pure water and in methanol/water mixtures by potentiometry method. The pK(a) values determined by this technique are in accordance with those values determined by ITC method in our laboratory and also with those other values from literature. Also dissociation enthalpies can be obtained from potentiometric pK(a) values by means of the Van't Hoff approach and these obtained values are in agreement with those ones determined directly by calorimetry in our laboratory. In the second part, we focused on studying about solubility. The Chasing Equilibrium method offers an alternative to the classical procedures to measure the solubility of compounds with acid-base properties. The method is fast and yields accurate results. In this work, the solubility of several compounds including acids and bases was determined through the Chasing Equilibrium approach. A study of experimental conditions in terms of sample weight was performed to measure solubilities. The study shows that only a limited range of weights, depending on the nature and solubility of the compounds, is adequate to obtain reliable results. In the third part of this work, the solubility vs. pH profiles of five ionizable drugs of different nature (a monoprotic acid, a monoprotic base, a diprotic base and two amphoteric compounds showing a zwitterionic species each one) have been determined through two different methodologies: the classical Shake-Flask (S-F) and the potentiometric Cheqsol methods using in both instances the appropriate Henderson-Hasselbalch (H-H) or derived relationships. The results obtained independently from both approaches are consistent. A critical revision about the influence of the electrolyte used as buffering agent in the S-F method on the obtained solubility values is also performed. Thus, some deviations of the experimental points with respect the H-H profiles can be attributed to specific interactions between the buffering electrolyte and the drug due to the hydrotrophic character of citric and lactic acids. In other cases, the observed deviations are independent of the buffers used since they are caused by the formation of new species such as drug aggregates (cefadroxil) or the precipitation of a salt from a cationic species of the analysed compound (quetiapine). In the forth part, the objective was to compare the dissolution behavior of tablets prepared from solid dispersions prepared in DMSO dissolvent with and without drug-carrier and also with and without surfactants in aqueous and acidic solutions. Amphotericine B was used as a model drug. Two types of carriers were used; mannitol, inulin. Solid dispersions with two different drug loads were prepared by freeze drying method. It was found that the drug dissolution rate in aqueous and acidic solutions was significantly increased in the presence of drug-carrier and surfactants. X-ray powder diffraction revealed that all solid dispersions were fully amorphous.
El objetivo del presente trabajo ha sido contribuir a establecer metodología robusta y de high throughput de interés en la etapa conocida como "Drug Discovery" que tiene lugar en los laboratorios farmacéuticos al inicio del proceso de desarrollo de nuevos fármacos. Este objetivo ha implicado la exploración de las posibilidades de la metodología potenciométrica establecida y comercializada por Sirius Analytical Ltd. para la determinación de las constantes de acidez y de la solubilidad de compuestos bioactivos y también un estudio sobre la mejora de la biodisponibilidad de un fármaco muy insoluble tomado como modelo mediante el aumento de su velocidad de disolución. En la primera parte de esta Tesis se han determinado potenciométricamente las constantes de disociación ácida y la variación de entalpía asociada de dos bases y dos ácidos tomados como modelo en agua pura y en mezclas de metanol/agua (0-60% w/w) a varias temperaturas (25-55°C). Esto ha implicado la puesta a punto de la estandarización del sistema potenciométrico en las condiciones de trabajo. Los valores de pK(a) determinados son concordantes con los que ofrece la literatura. Se han calculado también las entalpias de disociación en los distintos solventes binarios estudiados mediante la ecuación de Van't Hoff a partir de los valores experimentales de pK(a). La consistencia de los resultados obtenidos con los de la literatura, obtenidos directamente por calorimetría, confirma la robustez de la metodología. En la segunda parte de este trabajo, el estudio se centró sobre la determinación potenciométrica de la solubilidad de ácidos y bases mediante el método conocido como Chasing Equilibrium, como alternativa a los procedimientos clásicos de equilibración. El método es rápido y produce resultados precisos. Se ha realizado un estudio sobre las condiciones experimentales óptimas en términos de peso de la muestra para medir eficazmente la solubilidad. El estudio muestra que, en función de la naturaleza y solubilidad de los compuestos, existe un intervalo limitado de peso de muestra adecuado para obtener resultados fiables. En la tercera parte de la presente memoria, se estudian los perfiles de solubilidad en función del pH de cinco fármacos ionizables de naturaleza diferente, un ácido y una base monopróticos, una base diprótica y dos compuestos anfóteros que muestran una especie zwitteriónica cada uno. Se han determinado los perfiles de solubilidad mediante el método clásico de equilibración (Shake-Flak, S-F) y el potenciómétrico y, en ambos casos, se han utilizado las relaciones apropiadas de Henderson-Hasselbalch (H-H) o derivadas. Los resultados obtenidos de forma independiente por ambos métodos son consistentes. Se ha hecho un estudio crítico acerca de la influencia del electrolito utilizado como agente tampón en el método S-F en los valores de solubilidad obtenidos y se han observado algunas desviaciones de los puntos experimentales con respecto a los perfiles esperados que pueden ser debidas a interacciones específicas entre el electrolito tampón y el fármaco. En otros casos, las desviaciones observadas son independientes de los tampones utilizados y se pueden atribuir a la formación de nuevas especies tales como agregados iónicos del fármaco en estudio o la precipitación de una sal a partir de una especie catiónica del compuesto analizado. En la cuarta parte de esta memoria el objetivo ha sido estudiar la velocidad de disolución de comprimidos preparados a partir de dispersiones sólidas de un fármaco modelo con y sin portador del fármaco y también en presencia y en ausencia de tensioactivo en soluciones acuosas neutras y ácidas. Como fármaco modelo se estudió la Anfotericina B y se utilizaron como portadores manitol e inulina y como tensioactivos se ensayaron el deoxicolato de sodio (SDC) y el laurilsulfato de sodio (SLS). La difracción de rayos X reveló que el fármaco en estudio se hallaba en estado amorfo en todas las dispersiones sólidas estudiadas. Se puede concluir que la velocidad de disolución del fármaco se incrementa significativamente en presencia de portador y tensioactivo.

The Swedish government has decided that waste containing more than 0.1% mercury is to

be placed in a permanent repository in the bedrock1,10. To minimize the risk of spreading

mercury, elemental mercury must first be converted into a practically insoluble

compound. In a PhD investigation of stabilization attempts at SAKAB AB in Kumla

favorable conditions for conversion of mercury to cinnabar (the sparingly soluble sulphide

form of mercury and the naturally occurring mineral) was found. In a long-term study of

diffusion of mercury it was found that water solubility of mercury varied much, from 0.05

to 5 μmolL-1.

To be able to study the water solubility of mercury as detailed as possible a speciation

method was developed and verified. This investigation includes how different parameters,

like matrix properties and Hg0/solution ratios effects the solubility of mercury and how the

different species are distributed in the water phase. The total solubility of mercury is very

dependent of both the matrix properties and the Hg0/solution ratio.

Aqueous elemental mercury (Hg0

aq) is not as matrix dependent as the oxidized species.

However, trends show that a higher Hg0/solution ratio contributes to a higher solubility of

Hg0

aq. Factors like time, pH, ionic strength and degree of stirring, greatly effects the total

solubility of mercury. The concentration of the oxidized mercury species generated from

elemental mercury increases over time and is very dependent on the properties of the

matrix. After 18 hours the solubility of Hg0

aq ranges from 0.2 to 0.7 μmolL-1, depending

on Hg0/solution ratio. The solubility for the oxidized species has a much larger variation,

ranging from 0.1 to 28.6 μmolL-1. Among other things, because the composition and

redox potential of the matrix plays an important role in what mercuric complexes can be

expected to form, and contribute to the solubility.

Det har beslutats av regeringen att senast år 2010 skall kvicksilverhaltigt avfall med en

kvicksilverhalt på mer än 0.1% slutförvaras i en stabiliserad from djupt ner i berggrunden.

I en doktorsavhandling som genomförts på SAKAB AB i Kumla har det konstaterats att

det är möjligt att överföra elementärt kvicksilver till cinnober, den stabila sulfidformen av

kvicksilver som för övrigt är ett naturligt förekommande mineral. Experiment som pågått

under lång tid för att studera det elementära kvicksilvrets diffusion under olika

omständigheter har också utförts. De uppmätta halterna i vattenfasen har varierat mycket,

från 0.05 till 5 μmolL-1. Det är vad som ligger till grund för det här arbetet.

För att kvicksilvers löslighet skall kunna studeras fullt ut har en specierings metod

vidareutvecklats och verifierats att den fungerar. Studien innefattar hur lösligheten av

kvicksilver påverkas av olika parametrar, som till exempel; matriser med olika egenskaper

och olika kvicksilver/vatten kvoter, samt hur fördelningen mellan oxiderade species och

det elementära kvicksilvret är i vattenfasen (Hg0

aq). Den totala lösligheten av kvicksilver

beror dels av matrisens egenskaper och mängden kvicksilver i förhållande till mängden

vätska. Lösligheten av Hg0

aq är inte lika beroende av matrisen som de oxiderade species.

Däremot finns trender som visar att högre Hg0/lösning kvot bidrar till en aningen högre

löslighet av Hg0

aq. Tid, konduktivitet, pH och omrörning spelar stor roll för vilken

totalhalt och hur stor andel oxiderade species man får i vattenfasen. Lösligheten av Hg0

aq,

efter 18 timmar, varierar mellan 0.2 till 0.7 μmolL-1, beroende på Hg0/lösning kvoten.

Efter 18 timmar är lösligheten för de oxiderade species mycket mer varierande, från 0.1

till 28.6 μmolL-1. Detta beror bland annat på att matrisens sammansättning och redoxpotential

spelar en viktig roll för vilka komplex som kan bildas med kvicksilverjonerna

och på så sätt bidra till en ökad löslighet.

An investigation of the sodium aluminate-sodium nitrate system was conducted. The effect of sodium nitrate on the solubility of aluminum is important to the retrieval of waste from the tanks at the Hanford nuclear facility located in the state of Washington. Experiments were performed on the NaAlO2 - NaNO3 - H2O system at 25?aC and 50?aC. The results obtained from these experiments were then compared to predictions from the Environmental Simulation Program (ESP, OLI Systems, Inc.) and available literature data. The presence of sodium nitrate increased the solubility of sodium aluminate in water. Sodium nitrate exhibited a greater effect on the solubility of sodium aluminate at higher temperature. Error analysis of the experimental data was performed and indicated that the experimental molalities were accurate to within an average of +3%. The measured data will be used to improve existing databases for ESP.

This thesis describes a series of studies of the physical behaviour of commercially important stabilizing additives in polyolefins. A series of nickelthiocarbamates have been synthesised and their solubilities measured as a function of temperature in linear hydrocarbon solvents, low density polyethylene and isotactic polypropylene. The results are compared with predictions from a regular solution model. The loss of three benzophenone UV-stabilizers from supersaturated solution has been investigated with the aim of determining whether the loss is a diffusion controlled blooming or involves phase separation. Our data shows this phenomenon is a diffusion controlled blooming process. The volatilities of these same UV-stabilizers have been measured as a function of temperature. The solubility of a typical hindered amine (Tinuvin 770) has been investigated in hydrocarbon solvents and in polypropylene by infrared methods. Low solubility values were obtained in all cases. The diffusion of Tinuvin 770 in polypropylene has been monitored by an infrared method developed for the purpose and the diffusion coefficient estimated over a range of temperatures. Litp.rature data on solubility of additives together with our own data are critically reviewed and the effect of structure on solubility is analysed. Data on the benzophenone additives allows prediction of loss times and mechanisms to be made for the first time.

The continuing need for improved assessment of risk from heavy metal contamination of the environment has prompted scientific interest in quantifying and predicting metal solubility, ‘lability’ and bioavailability. This has led to the development of new techniques to fractionate and speciate trace metals in soils. The objectives of the current study were to increase understanding of the effects of (i) soil properties, (ii) contaminant source and (iii) contact time on metal lability and solubility in soils. Multi-stable isotope dilution (ID) methods were used to determine the lability (E-values) of Ni, Cu, Zn, Cd and Pb in soils, alongside more traditional approaches employed for metal fractionation including single and sequential extraction procedures. Most of the work was undertaken using (i) archived soils amended by metal salts (MA soils; n=23) and (ii) topsoils collected from Nottingham, Wolverhampton and London (Urban soils; n=100). The resulting data was used first to quantify the factors affecting trace metal lability in the MA soils using a logistic (S-shape) model which described metal E-value primarily as a function of soil pH with secondary influences from other soil properties. It was apparent that mineral oxides were important fixation phases for Ni, Zn and Cd while Pb was strongly affected by organic matter in soils. This model, parameterised on soils contaminated originally by metal nitrate solution, was then applied to the Urban soils to reveal the extent to which contaminant source still controlled metal lability. A further investigation of the long-term effect of metal source on metal lability was pursued through a third dataset of rural roadside soils (n=42) which had received Pb mainly from petrol-derived and geogenic sources, defined by their isotopic signature. It was demonstrated that petrol-derived Pb remained more labile than Pb from the parent material, despite decades of contact, although both petrol-derived and geogenic Pb contributed to both the labile and non-labile fractions. In a fourth dataset, soils that had received Pb from sewage sludge amendment (n=16), the co-existence of high phosphate concentration from sewage sludge limited the magnitude and range of Pb lability, probably through formation of Pb-phosphate minerals. No consistent agreement was found between labile fraction of Pb and any single sequential extraction (SEP) fraction in all soils contaminated by Pb from multiple sources. Both empirical equations (extended Freundlich) and mechanistic models (WHAM-VII) were used to predict metal solubility in the MA and Urban soils. The advantage of using E-values (ME) over metal extractable by dilute nitric acid (MExt) to represent the reactive metal fraction in predictions of solubility was very clear for WHAM-VII, but not for the ‘locally parameterised’ Freundlich model. This was almost certainly due to the strong links between pH and E-value becoming subsumed into the coefficient nominally describing the direct influence of pH on metal solubility in the extended Freundlich equation. However, overestimation of the solution concentration from WHAM-VII was observed for all five metals, and strongly correlated with soil pH. Fractionation information from WHAM suggested that the source of the model’s underestimation of metal binding most likely lay with errors in the description of metal binding by Fe and Mn oxides for Ni, Zn and Cd and humic acid (HA) for Cu. An additional factor is the absence of potential binding phases in the WHAM model, such as particulate CaCO3, and the greater diversity of active adsorbents in soils at high pH values. WHAM is based on the assumption that all metal bound to HA is labile. However, in the current study, ‘non-labile’ Cu, Zn and Pb fractions were observed in suspensions of HA extracted from grassland and peat soils. These were quantified by measuring metal E-values and EDTA-extraction of HA-bound metal using size-exclusion chromatography (SEC) coupled to ICP-MS to separate free and HA-complexed metal forms. Evidence of time-dependent metal fixation by HA was found for all three metals during the course of a 40 and 160 day incubation study. The proportion of non-labile Cu held by HA could be 40-50%. The presence of a non-labile metal fraction held by HA may substantially invalidate the assumption of reversible equilibrium which is central to all current geochemical models of metal binding to humic substances.

This study has consisted of two related areas of research. The first area concerned the measurement of the proportions of gauche rotamer about C-C and C-O bonds ofpoly(ethylene oxide) (PEO) from NMR coupling constants. 3J HCCH and 3J HCOC couplings in 1,2-dimethoxyethane and bis-(2-methoxyethyl)ether, both model compounds for PEO, plus 3JHCCH in poly(ethylene oxide), have been obtained in five solvents by iterative fitting. The deduced proportions of gauche rotamers are higher than previous estimates, and higher still after allowance is made for the pentane effect. They fit well with gas phase electron diffraction data, with current gas phase theoretical calculations and with standard RIS parameters for the polymer. The influence of solvent arises more from its H-bond donor properties than in its dielectric. This study was undertaken partly in order to elucidate likely conformations of the glycosidic bond in the ensuing work on cellulose dissolution. The second area of research was concerned with the dissolution of cellulose in amine oxides. Courtaulds PLC have successfully used N-methylmorpholine-N-oxide (NMMO) to produce cellulosic spinning solutions. However, the interaction between cellulose and NMMO is not clearly understood. We have therefore sought to amplifY the understanding of this polymer-solvent interaction, first with optical microscopy experiments, and then with solution-state and solid-state NMR techniques. Optical microscopy experiments showed several different behaviours of ramie fibres (natural, highly crystalline cellulose I) as they dissolved in NMMO with added ~O. In 81.2 % NMMO solution, the fibres were observed to swell without dissolution, or burst into tiny fragments or else bend at certain regions creating a "zigzagging" pattern before dissolution. The rates of dissolution were also variable. Some amine oxides that are non-solvents for cellulose were also found to swell ramie, though in this case without subsequent dissolution. The changes in the proton NMR chemical shifts of NMMO and N-ethylmorpholine-N-oxide (NEMO), dissolved in dry DMSO-d6, on addition of water or methyl-P.o-glucopyranoside (a soluble model compound for cellulose) were used to obtain binding constants. The binding between methyl-P.oglucopyranoside and NMMO (a solvent for cellulose) is about twice as strong as the binding between the non-solvent NEMO and the same saccharide, under these conditions. In contrast, the binding between NEMO and water is stronger than that measured between NMMO and water. The stronger interaction of NMMO (relative to the interaction of NEMO) with the saccharide helps to explain its potency as a solvent for cellulose, but the reason for its occurrence, and the weakened interaction with water, is not fully understood. The carbon NMR shift differences of methyl-P.o-cellobioside on addition of various amine oxides (both solvents and non-solvents for cellulose) were found to be similar. We propose that the 1:1 interactions of all amine oxides with cellulose may be similar but that the competing interaction between amine oxide molecules decides if they become a solvent or non-solvent for cellulose. The variation of spin-lattice relaxation measurements on the cellobiose carbons upon addition of NMMO was also studied It indicates an increase of mobility of the C5-C6 bond in the presence ofNMMO. This implies the breaking ofH-bonds in this region. Solid-state NMR spectra (both CPMAS and HPDEC/MAS) were run on aliquots of cellulose samples in NMMO, taken out at various stages of the dissolution process. A faster disappearance of the C4 peak from the crystalline phase relative to the C4 peak from the amorphous phase suggests that the crystalline phase must first be penetrated by the solvent before dissolution. In contrast ramie treated with the non-solvent NEMO was found to have been converted from cellulose I to cellulose illr Theamorphous phase of ramie fibres treated with the non-solvent trimethylamine-N-oxide was found to increase at the expense of the crystalline phase, although in this case no cellulose ~ was detected. Evidently, some amine oxides that are non-solvents for cellulose can nevertheless penetrate between layers of cellulose that are held together by Vander Waals forces, even though they cannot pull apart adjacent chains of cellulose (necessary for dissolution to occur) that are held together by strong H-bonds.

Thesis submitted in fulfilment of the requirements for the degree Master of Technology: Dental Technology in the Faculty of Health and Wellness Sciences at the Cape Peninsula University of Technology, 2012
Statement of problem It is well documented that water sorption and water solubility by auto-polymerizing resins have a negative impact on their physical properties and may lead to harmful tissue reactions. The presence of residual monomer is often identified as the main cause for adverse tissue reactions. To optimize the polymerization reaction, the use of the proper powder/liquid ratio is recommended in the fabrication of a dental appliance. It is also recommended that a dental appliance should be soaked in water for at least 24 hours before delivery to a patient, in order to reduce the possible adverse effect. For auto-polymerizing resins, associated with higher residual monomer levels than heat-cured resins, soaking the appliance at elevated temperatures (65ºC for 60 minutes), would reduce the residual monomer content more efficiently than at room temperature. This requires additional processing conditions from the technician or dentist. Changing the powder/liquid ratios, deliberately or not, may modify the residual monomer content of the final product. A relationship exists between the levels of residual monomer and water sorption. Also, residual monomer leaching into the oral fluids may lead to adverse effects such as, oral tissue irritation or a delayed hypersensitivity reaction. Aim of the study The aim of this study was to evaluate the effect of different powder/liquid ratios and different water temperatures on the levels of sorption and solubility of an auto-polymerizing resin material used for denture bases. The null-hypothesis tested was that there is no difference in sorption and solubility among groups of specimens made from an auto-polymerizing resin material soaked in water at different temperatures and/or fabricated with different powder/liquid ratios. Material and methods Specimens were made from cold-cure pour-type denture base resin (Type 2, Class 2) using different powder/liquid ratios and soaked at different soaking temperatures. One group of specimens fabricated with the manufacturer’s recommended powder/liquid ratio and soaked in water at 37ºC, served as the control group for both experiments. Custom-made stainless steel moulds were used to fabricate resin disks, with a diameter of 50mm and a thickness of 0.5mm. For the temperature-controlled experiment, identical specimens were prepared and stored in distilled water at 37ºC; 45ºC; 55ºC and 67ºC. For the ratio-controlled experiment, the ratios were increased incrementally for each group, starting with a 10% increase, followed by a 15%; 20% and 25% increase in monomer. Water sorption and solubility were tested in accordance with ISO Standard 1567 (1999). Specimens were weighed before and after water immersion, and desiccation. Water sorption and solubility were calculated using the difference in wet and dry mass and the volume of the specimens. The water sorption and solubility results were analyzed by means of analysis of variance. For multiple comparisons, Bonferroni simultaneous confidence intervals (α=0.05) were applied. Results For the ratio-controlled experiment, water sorption mean values varied from 24.148 μg/mm3 to 25.1333 μg/mm3. Statistically significant differences in mean values were found between the following groups: 0%-10%; 0%-15%; 0%-25%; 10%-20%; 15%-20% and 20%-25% ratio groups (P<.0001). Water solubility mean values varied from 0.616μg/mm3 to 0.932μg/mm3. Statistically significant differences in mean values were found between the following groups: 0%-15%; 0%-20%; 0%-25% and 10%-25% and 20%-25% ratio groups (P<.0001). For the temperature-controlled experiment, water sorption mean values varied from 24.185μg/mm3 to 26.434μg/mm3. Statistically significant differences in mean values were found between the following groups: 37ºC-45ºC; 37ºC-55ºC; 37ºC-67ºC; 45ºC-67ºC and 55ºC-67ºC temperature-controlled experiments (P<.0001). Water solubility mean values, for the same experimental groups, varied from 0.616μg/mm3 to 2.752μg/mm3. Statistically significant differences in mean values were found among all the 6 pairs of groups (P<.0001). Despite statistical differences, the water sorption and water solubility values of the tested resin for both experiments and all groups were within the ISO Standard 1567 (1999) specification limits. Conclusion For the ratio-controlled experiment, there was an inverse relationship between the mean sorption and solubility values with an increase in liquid in the mixture: low water sorption levels are associated with high solubility levels. The lower water sorption and higher solubility results for more fluid mixtures could be related to initial and residual high monomer content characteristic of auto-polymerizing materials. These higher levels of free monomer are consequently released upon immersion in water; hence the higher water solubility levels. For the temperature-controlled experiment, a higher soaking temperature resulted in an increase in water solubility levels. The higher solubility levels could be attributed to the higher soaking temperatures causing higher or faster monomer diffusion from the resin material. Except for the 67ºC group, sorption is also lower with higher temperatures. It may be assumed that an additional polymerization process takes place and a subsequent more inaccessible polymer matrix is produced. For the 67ºC group, thermal expansion may explain the higher sorption level. Clinical Implications In terms of the sorption and solubility results, this auto-polymerizing pour-type resin may be used as a denture base resin. Even though statistical differences were demonstrated, the material satisfies the ISO 1567 (1999) requirements not only for auto-polymerizing but also for heat-polymerizing resins. Therefore, within limits, the mixture may be prepared more fluidly in order to improve flow of the material, without negatively affecting its sorption and solubility properties. Because solubility is higher at higher soaking temperatures, this property can be used to minimize monomer content of the appliance. Therefore, it is recommended that the dental appliance be soaked in warm water, below 67ºC, prior to delivery to the patient.