Disputats. Rheinische Friedrich-Wilhelms-Universität, 2002. / Haves kun i elektronisk udg.

Environmentally friendly processing of materials is becoming an increasingly important consideration in a wide variety of emerging technologies. Polymer processing,in particular, has benefited tremendously in this venue from numerous advances achievedusing high-pressure carbon dioxide (CO2) as a viscosity modifier, plasticizing agent,foaming agent, and reaction medium. Polymer processing in supercritical fluids has been a major interest for a portfolio of materials processing applications including their impregnation into porous matrices. Also, SCF solvents are being examined as a media for polymerization processes, polymer purification and fractionation, and as environmentally preferable solvents for solution coatings. Pressurized CO2 isinexpensive, sustainable, relatively benign, and versatile due to its gas-like viscosity and liquid-like densities, which can be controllably tuned through appropriate choice of temperature and pressure. Addition of high-pressure CO2 to polymer systems can have a profound impact on their thermodynamic properties and phase behavior, since the number of interacting species increases due to the high-pressures, so that the compressibility also increases, as well as the plasticity effects. Even then, polymers are only sparingly soluble in CO2 unless one uses an entrainer or surfactant. An addition of a liquid monomer co-solvent results in greatly enhanced polymer solubility in the supercritical fluid at rather mild conditions of lower temperatures and reduced pressures.The focus of this research is to measure, evaluate and model the phase behavior of the methyl methacrylate-CO2 and the poly (methyl methacrylate)-CO2-methyl methacrylatesystem, where methyl methacrylate plays role of a co-solvent. Cloud-point data are measured in the temperature range of 30-80ʻC, pressures as high as 300 bar, co-solvent concentrations of 27 and 48.4 wt% MMA, and varying PMMA concentrations of 0.1, 0.2,0.5, and 2.5 wt%. Solubility data is reported for these systems. The experimental results are modeled accurately using the Statistical Associating Fluid Theory (SAFT) for multi component polymer/solvent mixtures. The measured solubility data appears to be significantly different than previously published results by McHugh et al, Fluid Phase Equilibria, 1999. Thorough investigation, re-calibration of the equipment, and repetition of the measurements has proved that the measured data is entirely correct and the reference data is significantly off, which indirectly gives credit to this work and opens room for amendments of those results.

Pharmaceutical cocrystals use principles of crystal engineering for the design of crystalline forms of drugs and can improve their solubility, bioavailability, stability and other important properties without changing the efficacy of the drug. Herein reported are pharmaceutical cocrystals of two API's, caffeine and Pentoxifylline. Research has indicated that caffeine has the ability to reverse AB; plaque deposition in the brain (believed to be the primary cause of Alzheimer's pathogenesis) and thus revert memory and improve cognitive impairment. But owing to the fast absorption rate and short half life, a controlled release formulation of caffeine would be clinically beneficial. Thus, novel cocrystals of caffeine are presented with varying solubilities with respect to caffeine. The pharmaceutical cocrystals of caffeine used herein include: caffeine.cyanuric acid monohydrate, caffeine.syringic acid tetrahydrate, caffeine.chlorogenic acid and caffeine.catechin hydrate. Three caffeine cocrystals were prepared in our lab previously which include caffeine.ferulic acid, caffeine.ethyl gallate dihydrate and caffeine.caffeic acid. In addition, six caffeine cocrystal forms were reproduced from the literature and included in the solubility study: caffeine.quercetin, caffeine.salicylic acid, caffeine.1-hydroxy-2-napthoic acid, caffeine.gallic acid hemihydrate, caffeine.ellagic acid monohydrate and caffeine.coumaric acid. Dissolution studies were performed in aqueous media at room temperature. All of the cocrystals decreased the solubility of caffeine with the highest being a 278 fold decrease in the solubility of caffeine. Analysis of melting point, crystal packing efficiency and solubility of cocrystal former with solubility was also done to determine if they influenced the solubility. Presented herein are the results of the analyses. It was seen that solubility of the cocrystal former had no effect on the decrease in cocrystal solubility. Moreover melting point and solubility of the cocrystal could not be correlated probably due to the variability in the cocrystal formers. Crystal packing efficiency though did not show a high correlation with solubility but it was seen that highest solubility achieved by pure caffeine achieved the lowest crystal packing efficiency and vice versa suggesting its role in cocrystal solubility. Pentoxifylline is contraindicated for its use in autism. But owing to high solubility of the drug, a less soluble form of the drug would help in decreasing the half life and thereby help in forming a sustained form of the drug by modifying the inherent solubility of the API. Here, novel cocrystals of Pentoxifylline are presented with varying solubilities with respect to the API. The pharmaceutical cocrystals used herein include: pentoxifylline.benzoic acid, pentoxifylline.1-hydroxy-2-napthoic acid, pentoxifylline.salicylic acid, pentoxifylline.gallic acid, pentoxifylline. salicylamide, pentoxifylline.coumaric acid, pentoxifylline.caffeic acid and pentoxifylline.catechin hydrate. Dissolution studies were also performed in aqueous media at room temperature. All of the cocrystals decreased the solubility of Pentoxifylline with the highest being a 99 fold decrease in the solubility with pentoxifylline.coumaric acid. On analyzing melting point, crystal packing efficiency and relation of solubility of cocrystal former with solubility of cocrystal, as was done in the case of caffeine, the parameters showed no effect on solubility of the cocrystal.

Thermodynamics is important for the design of amine scrubbing CO₂ capture processes. CO₂ solubility and amine volatility in aqueous amines were measured at high temperature and pressure. A rigorous thermodynamic model was developed for MEA-CO₂-H₂O in Aspen Plus®. CO₂ solubility at 80-190°C was obtained from total pressure measurements. Empirical models as a function of temperature and loading were developed for CO₂ solubility from 40 to 160°C in aqueous monoethanolamine (MEA), piperazine (PZ), 1-methylpiperazine (1MPZ), 2-methylpiperazine (2MPZ), PZ/2MPZ, diglycolamine® (DGA®), PZ/1MPZ/1,4-dimethylpiperazine (1,4-DMPZ), and PZ/methyldiethanolamine (MDEA). The high temperature CO₂ solubility data for MEA is comparable to literature and compatible with previous low temperature data. For MEA and PZ, amine concentration does not have obvious effects on the CO₂ solubility. The heat of CO₂ absorption derived from these models varies from 66 kJ/mol for 4 m (molal) PZ/4 m 2MPZ and to 72, 72, and 73 kJ/mol for MEA, 7 m MDEA/2 m PZ, and DGA. The heat of absorption estimated from the total pressure data does not vary significantly with temperature. At 0-0.5 loading ([alpha]), 313-413 K, 3.5-11 m MEA (mol fraction x is 0.059-0.165), the empirical model of MEA volatility is ln(PMEA/xMEA) = 30.0-8153/T-2594[alpha]²/T. In 7 m MEA with 0.2 and 0.5 loading, PMEA is 920 and 230 Pa at 120°C. At 0.3-0.5 loading, the enthalpy of MEA vaporization, -[Delta]Hvap,MEA, is about 70-73 kJ/mol MEA. At 0.25-0.4 loading, 313-423 K, 4.7-11.3 m PZ (x is 0.078-0.169), the empirical model of PZ volatility is ln(PPZ/xPZ) = -123+21.6lnT+20.2[alpha]-18174[alpha]²/T. In 8 m PZ with 0.3 and 0.4 loading, PPZ is 400 and 120 Pa at 120°C, and 2620 and 980 Pa at 150°C. At 0.25-0.4 loading, -[Delta]Hvap,PZ is about 85-100 kJ/mol PZ at 150°C and 66-80 kJ/mol PZ at 40°C. [Delta]Hvap,PZ has a larger dependence on CO₂ loading than [Delta]Hvap,MEA in rich solution because of the more complex speciation/reactions in PZ at rich loading. Specific heat capacity of 8 m PZ is 3.43-3.81 J/(g•K) at 70-150°C. Two new thermodynamic models of MEA-CO₂-H₂O were developed in Aspen Plus® starting with the Hilliard (2008) MEA model. One (Model B) includes a new species MEACOOH and it gets a better prediction than the other (Model A) for CO₂ solubility, MEA volatility, heat of absorption, and other thermodynamic results. The Model B prediction matches the experimental pKa of MEACOOH, and the measured concentration of MEACOO-/MEACOOH by NMR. In the prediction the concentration of MEACOOH is 0.1-3% in 7 m MEA at high temperature or high loading, where the heat of formation of MEACOOH has effects on PCO₂ and CO₂ heat of absorption. Model B solved the problems of Model A by adding MEACOOH and matched the experimental data of pKa and speciation, therefore MEACOOH may be considered an important species at high temperature or high loading. Although mostly developed from 7 m MEA data, Model B also gives a good profile for 11 m (40 wt%) MEA. / text

Poly (Ethylene Oxide) (PEO, with a general formula (CH₂-CH₂-O)[subscript pi] ) is completely soluble in water at room temperature over an extremely wide molecular weight range and has been widely studied by experiment and theory. The objective of our work is to study the solubility behavior by the method of Monte Carlo simulation. The insertion factor lnB, which is equivalent to the infinite dilute Henry's Law Constant, is used to represent the solubility of various molecules in water. Our research started with simple fluid and aqueous solutions of small molecules including hard spheres, inert gases, hydrocarbons and dimethyl ether (DME, as a precursor for PEO). Solubility consists of a favorable energy term and an unfavorable entropy term. Against the common belief of entropy-dominating-hydrophobicity effect, it is actually the ability of the solute to interact with solvent (or the energetic factor) that dominates solubility. The solubility minimum appearing for both hydrophobic and hydrophilic solutes along the water coexistence curve is the result of competition between the favorable energy contribution and the unfavorable entropy contribution. Normal alkanes with carbon number from 1 to 20 have been modeled by LJ chains to study the solubility of non-polar polymer chains in water. Various constraints have been put on the LJ model to evaluate their effect on solubility. No significant difference was observed for LJ chain with or without fixed bond angles, but torsional interaction changed the chain solubility dramatically. The temperature and chain-length effect on chain solubility has been examined and it can be explained by the balancing between the intra-chain interaction and entropy penalty. By choosing the right torsional interaction parameters we may be able to reproduce by simulations the solubility minimum of normal alkanes at C₁₁. PEO was modeled by united atom chains with length up to 30. The most probable distance between two nearest ether oxygens in both vacuum and aqueous solutions matches the hydrogen bond length in bulk water. Hydrogen bonding plays an important role in the unique water solubility behavior of PEO since the water-PEO interaction effectively increases the total number of hydrogen bonds and results in a favorable change in energy. A trans-gauche-trans conformation along the O-C-C-O bonds does enable hydrogen bond formation between one water molecule and two nearest or next nearest ether oxygens. A helix structure is not required for the PEO to have favorable interactions with water. Two polymers with similar structure as PEO but are insoluble in water: Poly (methylene oxide) (PMO) and Poly (propylene oxide) (PPO) have been studied to compare with PEO. Their difference in structure from PEO, though slight, reduces the chance of hydrogen bond forming between water and chains so as to decrease the solubility. / text

The cocrystallization of two or more pure compounds by crystal engineering to create a new functional material is of a great academic and industrial interest. Pharmaceutical cocrystallization has allured a lot of attention by means of altering the physicochemical properties of Active Pharmaceutical Ingredient (API) such as solubility, stability and bioavailability. Crystal engineering of nutraceuticals can produce novel compounds such as pharmaceutical cocrystals. To establish the importance of nutraceutical cocrystallization and its use; polyphenols, a major class of nutraceuticals and potential disease preventing agents, are the appropriate targets. The work herein focuses on two polyphenols, protocatechuic acid and quercetin, which are strong antioxidants. The cocrystals of quercetin have been synthesized, aiming to modify its poor water solubility and bioavailability which limits its usage. On the other hand, cocrystals of water soluble protocatechuic acid are also prepared to establish its use as a cocrystal former. Seven novel cocrystals of protocatechuic acid and two novel cocrystals of quercetin are obtained and are characterized by FTIR, DSC (Differential Scanning Calorimetry), PXRD (Powder X-Ray Diffraction), single crystal x-ray diffraction and TGA (Thermo Gravimetric Analysis). The new crystal forms have also been studied via dissolution. Dissolution studies show alteration in solubility of a target molecule by its cocrystal irrespective of solubility of the cocrystal former. Overall, the study helps in understanding the role of crystal engineering and its utility.

Membrane separation technology has recently emerged as a potential alternative technique for removing higher hydrocarbons (C₃₊) from natural gas. For economic reasons, membranes for this application should be organic vapor selective materials such as poly(dimethylsiloxane) (PDMS) or poly(1-trimethylsilyl-1-propyne) (PTMSP). These polymers, often called solubility selective polymers, sieve penetrant molecules based largely on relative penetrant solubility in the polymer. The sorption and transport properties in such polymers have been reported previously. However, most studies present only pure gas sorption and transport properties. Mixture properties, which are important for estimating membrane separation performance, are less often reported. In addition, mixed gas sorption and diffusion data in such polymers, to the best of our knowledge, have never been investigated before. This research work provides a fundamental database of mixture sorption, diffusion, and permeation data in solubility selective polymers. Two solubility selective polymers were studied: poly(dimethylsiloxane) (PDMS) and poly(1-trimethylsilyl-1-propyne) (PTMSP). The vapor/gas mixture was n-C4H10/CH4. CH4 partial pressures ranged from 1.1 to 16 atm, and [subscript n-]C₄H₁₀ partial pressures ranged from 0.02 to 1.7 atm. Temperatures studied ranged from -20 to 50 oC. The pure and mixed gas [subscript n-]C₄H₁₀ and CH₄ permeability and solubility coefficients in PDMS and PTMSP were determined experimentally using devices constructed specifically for these measurements. The pure and mixed gas diffusion coefficients were calculated from permeability and solubility data. In rubbery PDMS, the presence of [subscript n-]C₄H₁₀ increases CH₄ permeability, solubility, and diffusivity. On the other hand, the presence of CH₄ does not measurably influence [subscript n-]C₄H₁₀ sorption and transport properties. The [subscript n-]C₄H₁₀/CH₄ mixed gas permeability selectivities are lower than those estimated from pure gas measurements. This difference is due to both lower solubility and diffusivity selectivities in mixtures relative to those in pure gas. Plasticization of PDMS by [subscript n-]C₄H₁₀ does little to n-C4H10/CH₄ mixed gas diffusivity selectivity. Increases in mixed gas permeability selectivity with increasing [subscript n-]C₄H₁₀ activity and decreasing temperature were mainly due to increases in solubility selectivity. Unlike PDMS, the presence of [subscript n-]C₄H₁₀ decreases CH₄ permeability, solubility, and diffusivity in PTMSP. The competitive sorption and the blocking effects significantly reduce CH₄ solubility and diffusion coefficients in the polymer, respectively. However, similar to PDMS, the presence of CH₄ has no measurable influence on [subscript n-]C₄H₁₀ sorption and transport properties. [subscript n-]C₄H₁₀ /CH₄ mixed gas permeability selectivities in PTMSP are higher than those determined from the pure gas measurements. This deviation is a result of higher solubility and diffusivity selectivities in mixtures relative to the pure gas values. Mixed gas permeability, solubility, and diffusivity selectivities in PTMSP increased with increasing [subscript n-]C₄H₁₀ activity and decreasing temperature. The partial molar volumes of [subscript n-]C₄H₁₀ and CH₄ in the polymers were determined from sorption and dilation data. The dilation isotherms of PDMS and PTMSP in mixtures agree with estimates based on pure gas sorption and dilation measurements. The partial molar volumes of n-C4H10 and CH4 in PDMS are similar to those in liquids. In contrast, the partial molar volumes of [subscript n-]C₄H₁₀ and CH₄ in glassy PTMSP are substantially lower than those in liquids. Several models were used to fit the experimental data. For instance, the FFV model, the activated diffusion model, and the Maxwell-Stefan model were employed to describe the mixture permeability data in PDMS. Based on the Maxwell-Stefan analysis, the influence of coupling effects on permeation properties in PDMS were negligible. The dual mode sorption and permeation models were used to describe the mixed gas data in PTMSP. The dual mode permeability model must be modified to account for [subscript n-]C₄H₁₀ -induced reductions in CH₄ diffusion coefficients (i.e., the blocking effect). The FFV model provides poor correlations in PTMSP. There seems to be other factors, besides FFV per se, contributing to the temperature and concentration dependence of diffusion coefficients in PTMSP.

The removal of higher hydrocarbons from natural gas streams is an important separation that has been identified as a growth area for polymer membranes. An ideal membrane material for this separation would be more permeable to higher hydrocarbons (i.e., C3+ compounds) than to CH₄. This allows the CH₄ rich permeate to be retained at or near feed pressure, thus minimizing the requirement for repressurization followingmembrane separation. A polymer which demonstrates the ability to separate vapor from gases with high efficiency is poly [1-(trimethylsilyl)-1-propyne] (PTMSP). PTMSP is a stiff chain, high free volume glassy polymer well known for its very high gas permeability and outstanding vapor/gas selectivity. However, PTMSP is soluble in many organic compounds, leading to potential dissolution of the membrane in process streams where its separation properties are of greatest interest. PTMSP also undergoes significant physical aging, which is the gradual relaxation of non-equilibrium excess free volume in glassy polymers. Crosslinking PTMSP with bis(azide)s was undertaken in an attempt to increase the solvent resistance and physical stability of the polymer. A fundamental investigation into crosslinking PTMSP with a bis(azide) crosslinker was the focus of this thesis. Pure gas transport measurements were conducted with N₂, O₂, CH₄, C₂H6, C₃H₈, and n-C₄H₁₀ over temperatures raging from -20°C to 35°C and pressures ranging from 0 to 20 atm. Mixed gas permeation experiments were conducted using a 98 mol % CH₄, and 2 mol % n-C₄H₁₀ mixture. The mixed gas permeation experiments were conducted at temperatures ranging from -20°C to 35°C, and pressures ranging from 4 to 18 atm. Inorganic nanoparticles such as fumed silica (FS) were added to uncrosslinked and crosslinked PTMSP, and the effects of their addition on the transport properties were investigated. Crosslinking PTMSP with bis(azide)s increases its solvent resistance, and crosslinked films are insoluble in common PTMSP solvents such as toluene. At all temperatures, the initial pure and mixed gas permeabilities of crosslinked PTMSP films are less than those of uncrosslinked PTMSP. This decrease in permeability is consistent with the fractional free volume (FFV) decrease that accompanies crosslinking. Pure gas solubility coefficients are relatively unaffected by the crosslinking process, so the decrease in permeability is caused by decreases in diffusivity. The addition of FS nanoparticles increases the initial pure and mixed gas permeabilities of uncrosslinked and crosslinked PTMSP. The pure gas permeabilities and solubilities of all PTMSP films increase when the temperature decreases, while the diffusivities decrease. The rates of change in pure gas transport properties with temperature is similar for all films, so the temperature dependence of pure gas transport properties of PTMSP is unaffected by the addition of crosslinks or FS. The aging of uncrosslinked and crosslinked PTMSP films was investigated by monitoring N₂, O₂ and CH₄ permeabilities and FFV over time. The FFV and permeabilities of crosslinked films decreased over time, so crosslinking did not arrest the physical aging of PTMSP, as has been previously reported, and these differences in aging observations are likely to be a consequence of differences in post film casting thermaltreatments. The addition of 10 wt % polysiloxysilsesquioxanes (POSS) nanoparticles decreases the permeabilities of uncrosslinked and crosslinked PTMSP by approximately 70 %, and the permeability and FFV values of the resulting nanocomposite films were stable over the course of 200 days. In all PTMSP films, the mixed gas permeabilities of n-C₄H₁₀ increase with decreasing temperature, while the mixed gas CH₄ permeabilities decrease with decreasing temperature. As a result, the mixed gas n-C₄H₁₀/CH₄ permeability selectivities increase with decreasing temperatures. The addition of crosslinks and FS nanoparticles to PTMSP decreases the mixed gas n-C₄H₁₀/CH₄ permeability selectivities, and changes in the free volume characteristics of PTMSP caused by crosslinking and FS nanoparticles are thought to reduce the blocking of CH₄ permeation by n-C₄H₁₀. / text

Dispersing co-crystals in a polymeric carrier may improve their physicochemical properties such as dissolution rate and solubility. Additionally co-crystal stability may be enhanced. However, such dispersions have been little investigated to date. This study focuses on the feasibility of dispersing co-crystals in a polymeric carrier and theoretical calculations to predict their stability. Acetone/chloroform, ethanol/water, and acetonitrile were used to load and grow co-crystals in a HPMCAS film. Caffeine-malonic acid and ibuprofennicotinamide co-crystals were prepared using solvent evaporation method. The interactions between each of the co-crystals components and their mixtures with the polymer were studied. A solvent evaporation approach was used to incorporate each compound, a mixture, and co-crystals into HPMCAS films. Differential scanning calorimetry data revealed a higher affinity of the polymer to acidic compounds than their basic counterparts as noticed by the depression of the glass transition temperature (Tg). Moreover, the same drug loading produced films with different Tgs when different solvents were used. Solubility parameter values (SP) of the solvents were employed to predict that effect on the depression of polymer Tg with relative success. SP values were more successful in predicting the preferential affinity of two acidic compounds to interact with the polymer. This was confirmed using binary mixtures of naproxen, flurbiprofen, malonic acid, and ibuprofen. On the other hand, dispersing basic compounds such as caffeine or nicotinamide with malonic acid in HPMCAS film revealed the growth of co-crystals. A dissolution study showed that the average release of caffeine from films containing caffeine-malonic acid was not significantly different to that of films containing similar caffeine concentration. The stability of the caffeine-malonic acid co-crystals in HPMC-AS was prolonged to 8 weeks at 95% relative humidity and 45°C. The theory developed in this project, that an acidic drug with a SP value closer to the polymer will dominate the interaction process and prevent the majority of the other material from interacting with the polymer, may have utility in designing co-crystal systems in polymeric vehicles

A major challenge affecting the likelihood of a new drug reaching the market is poor oral bioavailability derived from low aqueous solubility. Nanocrystals are rapidly becoming a platform technology to address poor solubility issues, although several challenges including stabilisation and control of particle size distribution for nanosuspensions still need to be addressed. The aim of this study was to revisit the simplest approach of re-precipitation and to identify the critical parameters, including the effect of different stabilisers as well as process conditions. We utilised a combined approach of both experiments and molecular modelling and simulation, not only to determine the optimum parameters but also to gain mechanistic insight. The experimental studies utilised three rather distinct, relatively insoluble drugs, the hypoglycaemic glibenclamide, the anti-inflammatory ibuprofen, and the anti-malarial artemisinin. The choice of crystal growth inhibitors/stabilizers was found to be critical and specific for each drug. The effect of the process variables, temperature, stirring rate, and the solute solution infusion rate into the anti-solvent, was rationalized in terms of how these factors influence the local supersaturation attained at the earliest stages of precipitation. Coarse grained simulation of antisolvent crystallisation confirmed the accepted two step mechanism of nucleation at high supersaturation which involves aggregation of solute particles followed by nucleation. Recovery of nanocrystals from nanosuspensions is also a technical challenge. A novel approach involving the use of carrier particles to recovery the nanocrystals was developed and shown to be able to recover more than 90% of the drug nanocrystals. The phase stability of nanocrystals along with bulk crystals for the model compound glycine was explored using molecular dynamics simulation. The simulations were consistent with experimental data, a highlight being the β phase transforming to the δ phase at temperature >400K and 20kbar respectively, as expected. Nanocrystals of α, β and γ glycine, however did not show any phase transformation at high temperature. In summary the study demonstrates that standard crystallization technology is effective in producing nanocrystals with the primary challenge being physico-chemical (rather than mechanical), involving the identification of molecule-specific crystal growth inhibitors and/or stabilizers. The developed nanocrystal recovery method should enable the production of nanocrystals-based solid dosage forms. The molecular simulation studies reveal that crystal-crystal phase transformations can be predicted for hydrogen-bonded systems.