Projects

The aim of the project is to develop an innovative analytical methodology for predictive evaluation of novel oral medicines. The market gap is the need to apply techniques enabling complex evaluation of medicines at the earliest possible stage of development. The synergy of the capabilities of consortium members will enable the development of a dedicated analytical platform for biopharmaceutical characterisation of novel medicines including:

• Revolver – a device for simulating the physicochemical conditions of the digestive tract
• novel methodology for bio relevant simulation of the application route
• explanation of the mechanism controlling the drug delivery of medicines on the molecular level
• dedicated and open software for biopharmaceutical evaluation of medicines

The novel methodology will shorten and rationalize the development and evaluation process of oral medicines and analysis of high potent and hazardous drugs. The key product innovation will be the Revolver device supported by a cutting edge open access hardware and software platform for automation, data acquisition, communication with laboratory information management systems and pharmacokinetic calculations. The project also includes development, formulation and testing of oral dosage forms based on dedicated sugars and polymers. Both, novel formulations and excipients will also represent product innovations that will be developed in course of further R&D activities of consortium members. The target group for the methodology developed are large and medium-size pharmaceutical and biotech companies as well as research institutes involved in the development of innovative and generic medicines and dietary supplements. Implementation of the project results will take place first in the Republic of Poland, and then in an international markets. It will be realized in two basic ways: through the sale of an innovative device and in the form of a service -testing of medicines using the developed methodology.

Nanomaterials are currently one of the most explored class of materials. This enormous interest results from their unusual properties often different than the one observed in case of bulk materials. In fact, the spatial nanometric restriction becomes a novel tool that provides outstanding opportunity of producing materials of unique physical properties and morphologies satisfying the industrial requirements (i.e., solar batteries, fuel cell, or drug carriers). Nevertheless, it should be added that apart from the significant industrial potential of the nanometerials a better understanding and eventual correlations between macroscopic properties and behavior of spatially restricted confined matter seems to be a key scientific problem. In this context, it is worthwhile to stress that nanoscale conditions can be a powerful novel tool to investigate the glass transition phenomenon, one of the most fundamental unsolved problem of condensed matter physics.

The main aim of this project is to provide novel experimental data crucial for filling a missing gap in our understanding of the behavior (especially the variation in the molecular dynamics and the glass transition temperature) of the materials confined within porous materials (under so-called two-dimensional, 2D, confinement). By the combination of various experimental techniques, i.e., dielectric spectroscopy, calorimetry, as well as contact angle and surface tension measurements, we are planning to investigate the correlation between the variation in the molecular dynamics of various materials infiltrated within porous template and their interfacial energy, γSL, where a special attention will be paid to various polymers in particular, characterized by different topologies, molecular weight and terminal groups. Especially, we would like to investigate impact of the changes in the strength of intramolecular interactions between the constrain medium made of different materials, i.e., silica and zirconium oxide, and the confined materials on the molecular dynamics of selected systems. It seems interesting to explore if the similar confinement effects can be observed in these templates do these effects scale with γSL. Additionally, we would like to explore the correlation between the finite size and the surface effects since our preliminary studies showed that both of them seem to be directly entangled. Last but not least, we are planning to explore the mechanism and the kinetics of the density perturbation of infiltrated materials observed at some specific temperature conditions. Especially, we would like to examine if they are either the same or different for both the low molecular weight glass forming liquids and polymers.

It should be pointed out that all aspects we are going to study obey fundamental problems of the physics of condensed matter intensively investigated in the literature and can be separately considered as a subject of the prepared proposal. Additionally, they open new ways and possibilities of the perception and  understanding of the behavior of the spatially restricted systems.

We are strongly convinced that the planned systematic and comprehensive studies on various low and high molecular weight glass formers (including linear and star-shaped polymers) infiltrated within porous membranes made of different materials (i.e., silica, alumina, zirconium oxide) and characterized by various pore size, d, and the strength of host-guest molecular interactions. We believe that detailed studies on various systems by means of standard experimental techniques, as Broadband Dielectric Spectroscopy and Differential Scanning Calorimetry (DSC, including thermal-modulated DSC, TMDSC) and supplemented by other methods, i.e., FTIR and Raman spectroscopies, including the pioneering measurements by Atomic Force Microscopy (AFM) and XRD method, give us a unique opportunity to get insight in the microscopic structure and density fluctuations of the confined system allowing to make some more universal conclusions and deliver a model to predict the variation in molecular dynamics and glass transition temperature of the low and high molecular weight glass formers incorporated into pores.

The planned actions are of a great importance in the development of the basic knowledge on the behavior of soft matter under confinement, especially in a better understanding of the relationship between finite size, surface effects (including the surface tension and the interfacial energy) and density fluctuations on the variation in the molecular dynamics and the glass transition temperature, Tg. These aspects seem to be of fundamental significance to verify current approaches used to explain the origin and nature of the properties and behavior of confined materials.

The main goal of the project is the use of a new, innovative method of polymer synthesis based on the photo- and photochemically-induced polymerization conducted under high pressure conditions. The project aims to investigate the impact of high pressure on polymerizability and reaction kinetics of a specific group of so-called “less-activated monomers” possessing ionic and non-ionic character and additionally characterized by the presence of sterically congested functional groups in their structure. Moreover, the use of compression of the reaction system and light as both the freeradical generator and mediator of polymerization will help to reduce or eliminate defects in classical free-radical polymerization (FRP) and controlled polymerization methods (CRP). In the case of FRP, it will be possible to reduce the dispersity of the resulted polymers, whereas in the case of CRP methods, to increase the reaction rate and obtain high molecular weight polymers. In addition, the project provides for the determination of the impact of high pressure on the physico-chemical and rheological properties (intrinsic viscosity, thermal stability, stress relaxation) of the produced macromolecules, as well as the creation of direct correlation between their parameters, e.g. the effect of molecular weight on stress relaxation and viscoelastic or thermodynamical properties of polymers). The “less-activated monomers” such as N-vinylimidazoles, N-vinylpyrrolidone, vinyl acetate, or N-vinyltriazoles and N-vinylcarbazole are an interesting group of compounds that have found application in many fields of science including medicine, biochemistry as well as electrical and optoelectronics. These monomers, due to their chemical structure (unconjugated vinyl group) are characterized by lower activity and polymerization in comparison to the group of “more-activated monomers (MAMs)”, such as (meth)acrylates and styrene derivatives. The above properties make it impossible to obtain high monomer conversions, as well as polymers with a high degree of polymerization as a result of polymerization of LAMs CRP methods, which results in low or moderate molecular weights. In this project, selected monomers from the LAMs group, e.g. N-vinylpyrrolidone and ionic and non-ionic N-vinyltriazoles, which additionally will contain sterically hindered functional groups, will be subjected to direct photo- and/or photochemically initiated high-pressure conventional and controlled polymerizations. This will allow obtaining macromolecules with strictly defined parameters by applying the metal-free method and investigating the effect of high pressure on their polymerizability. Additionally, it is worth paying attention to one of the research aims included in the project, i.e. to create a direct relationship between the basic parameters of the polymers. Recently, understanding the correlation between basic properties of polymers including those possessing features of poly(ionic liquid)s e.g. intrinsic structure and thermomechanical and rheological properties or conductivity have aroused the attention of scientists. Moreover, for this purpose polymers with well-defined structures and targeting specific properties are absolutely required. In this context, one can mention that there is a lot of important information about the behavior of ionic polymers missing in the literature. Just to remind that there are only a few papers on the evolution of the glass transition temperature vs molecular weight in these materials. Once polymers of well-defined structure and narrow dispersities are synthesized one can open discussion about the mechanisms of charge transport in ionic polymers e.g. ionic poly(N-vinyltriazoles) or mechanism of release of drugs from polymer matrices in biocompatible polymers such as poly(N-vinylpyrrolidone), which is a matter of current investigations. One can add that this point seems to be crucial in better designing and development of polymers of enhanced conductivity for possible applications as solid state electrolytes or polymers characterized by extended release time in controlled drug delivery systems.

The main idea of our proposal is to study impact of high pressure and spatial confinement, implemented by application of the nanoporous materials  of controlled size, geometry and functionality, on the radical, step growth, ring opening polymerization as well as isomerization in saccharides and representative active pharmaceutical ingredients (API). The current research on the saccharides and API’s show that chemical interconversion can be induced by partial amorphization, irradiation, humidity, temperature variation. As a consequence of that drastic change in basic physicochemical properties and therapeutic activity of pharmaceutical can be noted.  It is worth to mention that until now not much was done to describe kinetics, fully understand and eventually avoid this undesired  process occurring in the solid state. On the other hand over few last decades significant progress in synthesis of the macromolecular materials have been achieved. For this purpose many sometimes sophisticated methods relying  on the application of combination of initiators, catalysts, solvents and monomers were developed to gain better control over the reaction and the final product.

Current studies indicate that similar or even better effects can be reached by application of high pressure or carrying out reaction under spatial confinement. It is worth to mention high pressure works done by Prof. Bini and Schettino who showed that by combination of various thermodynamic conditions supported by laser irradiation one can synthesize low (LDPE), high (HDPE) density polyethylene or pure transpolybutadiene. In this context,  it must be reminded that synthesis of the latter macromolecule with the use of conventional methods seems to be very hard task.

Prof. Uemura studied impact of porous polymers on the kinetics and properties of the produced macromolecules. It was shown that by variation of nanoporous matrices one can obtain polymers of lower or higher molecular weight and polydispersity index (PDI). What is more stereo selectivity of the reaction was significantly improved  One can add that as opposite to polymerization under confinement there is only few works in literature touching kinetics aspects of isomerization under confinement.

In the framework of this proposal we would like to carry out multi task  and systematic studies on the impact f high pressure and spatial confinement on:

1. Step growth polymerization involving different kinds of epoxy and amine hardeners
2. Ring Opening Polymerization in lactones, such as δ-valerolactone, ε-caprolactone, γ-butyrylolactone, α-angelica
3. Radical polymerization of novel, synthesized for the purpose of this project monomeric ionic liquids
4. Mutarotation and solid state isomerization involving reactions activated by proton transfer, cis-trans interconversion, and finally racemization in saccharides, glibenclamide, nucleosides, ibuprofen respectively

The first part of our work is devoted to high pressure polymerization in very important class of monomers. It should be added that due to special physicochemical properties of produced macromolecules they find application in wide range of applications. One can mention that epoxy-amine resins find a lot of applications in the aviation factories, polylactones attracted attention of medicinal industry, because of their biodegradation abilities. Finally polymerizeable ionic liquids became very important group of materials giving an unique opportunity to synthesize hybrid materials sharing polymeric and ionic liquids properties. It turns out that high pressure polymerization of listed above monomers is not discussed in literature at el. It is related to many different factors. Basing on our earlier experience supported  by the literature one can expect that systematic high pressure studies will contribute significant to the progress of knowledge and to development of new green ways of synthesis of macromolecules. For this purpose we plan to carry out measurements at varying thermodynamic conditions to optimize polymerization and to check basic physicochemical properties such as molecular weight, PDI, structure, dc conductivity, of produced polymers as well as concentration of isomers in the case of isomerization interconversion.  In addition we also would like to determine constant rates, activation energy and volume for the reactions carried out at different T and P. These parameters will be very useful to discuss mechanism of chemical reactions occurring at high pressures.  The other motivation of these studies is to propose a new theoretical model to predict constant rates and activation volume at varying pressures and temperatures. It seems to be crucial to avoid or eventually suppress side reactions and to predict the main pathways of  polymerization or isomerization. In this context one can add that at high pressures reaction of the lowest activation volume are preferred. For this purpose entropic Avramov model, very often used to describe molecular dynamics of glass formers at different T and P , will be applied. It is worth to mention that earlier Correzzi as a first adopted Adam-Gibbbs entropic model to describe experimental data obtained upon ambient pressure polymerization of epoxy-amine resins.

The other part of our project will be devoted to studying impact of nanoporous materials on the isomerization and polymerization. We wish to determine the influence of varying geometry, functionality and pore diameter on the kinetics, properties of formed polymers as well as distribution of isomers in the case of polymerization and isomerization. It must be stressed that nanoporous materials offer unique opportunity to control morphology of the synthesized macromolecules on the nanometer scale. Hence nanofibers and nanorods of different diameters and properties can be recovered. Furthermore such materials can find numerous applications in medical, optical and electronic nanotechnologies.  Our studies will be also important in case of API’s. We would like to verify is it possible to limit or even suppress mutarotation or isomerization in saccharides and pharmaceuticals respectively by varying functionality, degree of confinement.   The outcome of our research supported by dissolution measurements may contribute to development of much safer nanoformulations of drugs characterized by enhanced pharmacological parameters.  The other very interesting issue we would like to address is impact of negative pressure which surely develops in nanoporous materials on the progress of studied chemical reactions. It is worth to mention that there are many theories trying to explain shorter constant rates for the reaction carried out under confinement. Many different mechanism of such reaction are considered. However none of these approaches takes into account negative pressure as another significant variable in controlling progress of chemical conversion.. In this context it is worth to remind that there are reports indicating that negative pressure inside nanoporous materials is even higher than P>80 MPa. Herein one can also mention that our very recent  studies on dynamics of glass formers in AAO uniaxial membranes confirm this supposition.  It seems to be very important to explain the role of negative pressure on the progress of isomerization and polymerization. It will enable to revise old theories and construct new one more realistic concept of chemical conversion in pores.

final and simultaneously the most risky point of our project concerns pioneering real high pressure studies on polymerization and isomerization under confinement. We expect that by combination of both variable significant progress in control over chemical reactions will be gained.  We are going to determine constant rates, activation energy and volume  to elucidate mechanism of these reactions carried out at so extreme conditions.  In addition we also plan to study interplay of both high pressure and degree of spatial confinement on the structure, morphology, of the recovered products, These research may lead to development of new ways of synthesis of nanopolimers of unique structure and properties.

The planned project, what is worth emphasising, has an interdisciplinary character and covers different aspects of chemistry of materials at high pressures and under spatial confinement.  We are going to go much beyond the current state of the art and focus on description of fundamental properties and mechanism of polymerization as well as the most conventional chemical isomerization of some classical compounds including saccharides and APIs undergoing proton activated processes. The main idea of our proposal is to gain as much control over the chemical interconversion and optimizing physicochemical properties, structure and morphology of the recovered products.

Systematic studies will surely contribute to progress in basic knowledge and may be useful in synthesis of macromolecules, controlling undesired isomerization of API’s. We are also convinced that our studies on the confined systems may provide strong background to development of new ways of synthesis of polymeric nanofibers and nanowires and safe drug nano formulations of enhanced bioavailability.

The main purpose of this project is to study the phase transition and molecular dynamics in the supercooled and glassy state in low molecular weight liquids as well as polymers under 1 D and 2 D spatial confinement. This issue seems to be extremely important in the context of the current discussion on the molecular origin of the glass transition which is one of the fundamental unresolved problem of condensed matter physics. It is worth to mention that upon cooling of the liquids drastic increase in viscosity and slowing down of the dynamics at relatively narrow range of temperatures close to Tg is observed. To explain this experimental universal finding  different  theoretical concepts were developed. One of the most interesting is the one proposed by Adam and Gibbs who related increased length scale of cooperativity (ξ), they called it cooperatively rearranging regions (CRR)) as underlying mechanism of sudden and huge increase  in viscosity. On the other hand spatial confinement offers unique opportunity to go even below that predicted value of ξ. Hence, the new experimental way to study molecular dynamics and glass transition phenomenon emerged.. However as shown recently, the situation is far more complicated due to perturbation introduced by the surface and interface substrate- liquid effects. As a consequence, the shift of the dynamic glass transition does not have to be necessarily just a  function of the degree of spatial restriction. Thus positive or negative shift of the phase transition can be recorded. What is more current papers on the dynamics of thin films made of polymers present completely contradictory results. It should be added that there are works that show that segmental relaxation does not change even for the single coil of polymer while others show that Tg can be shifted by more than 50 K. Hence, both results seems to be in clear conflict leading to a hot debate on the nature of the glass transition temperature. New theoretical models are proposed and developed to account experimental observations. The newest research indicating strong heterogeneous structure of the confined liquids put these results in new context and  may be the key to understand these discrepancies  It is worth to mentions that our studies carried out in pores showed that there are at least two fraction of molecules i.e. interfacial and core ones which demonstrate completely different dynamics as revealed by dielectric and calorimetric measurements This observation agree with the two layer model by Mc Kenna and Kremer. However our data indicated strong interplay between core and interfacial mobility as well as thermal history of the sample leading to different shift of the dynamic glass transition temperature. We would like to continue this research to see if this observation is universal for the all kind of glass formers. Beside we would like to develop concept of negative pressure in pores proposed by Zhang, discussed also by Prof Patkowski and furthermore criticized by Mc Kenna, Simon. Our combined high pressure and confinements preliminary studies indicated undoubtedly that this effect can be quite significant contributing to the shift of the Tg in pores. What is more it seems that basing on the data obtained under confinement one can get direct information about the repulsive index in Lennard-Jones potential describing interaction in the investigated system. This is remarkable opportunity since this information are usually derived from theoretical computations or high pressure complicated measurements. Moreover, we would like to see the of impact 1D or 2 D confinement, strength of interactions substrate-sample, topology and geometry of the matric, on the physical aging, dynamics of secondary relaxation processes, supramolecular structures, kinetics of crystallization and morphology of the recovered crystals. As a final point we are going to make pioneering measurements on the dynamics of confined system at high pressure  to make more complete picture of the relationship between structure, density packing, molecular dynamics and the glass transition phenomenon. This kind of research seems to be fundamental in the context of current discussion in the scientific literature.

Within the framework of this project 1D and 2 D confined system will be investigated with the use of Dielectric, FTIR, Raman spectroscopies supported by the Differential, Temperature Modulated Scanning Calorimetry (DSC, TMDSC), and  Atomic Force Microscopy. We also plan to run positon annihilation measurements. The data obtained from these techniques enable us to obtain complementary information on molecular dynamics, intermolecular interactions, as well as anisotropy in density packing, thermodynamic properties of confined matter which will further serve to build more complete picture of the structure of confined and its impact on the measured direction and shift of the dynamic glass transition temperature. Consequently, we shall come closer to universal description of the glass transition phenomenon. We are convinced that systematic and comprehensive studies will serve as a base for a development of the new nanotechnologies covering application of nanoporous materials as effective drug carriers, template for the synthesis of the new polymorphic forms where control over topology and morphology of the crystal will be done on the nanometer scale. This furthermore may lead to development of the new nanomaterials technologies.