Here below each project you can find the name of academic supervisor(s), his university/department and project assignments to research area(s) from five key domains in The Parc: Solid state chemistry, Preformulation and solid state analysis, Drug design and process, Biopharmacy and Preclinical in vivo testing. For more information on a specific Ph.D. project, you can contact us at info@theparc.eu or you can contact the academic supervisor directly (find email below each project description).
Do you have your own original research idea for a Ph.D. project which could fit into the scientific scope of The Parc? Do not hesitate to contact us at info@theparc.eu. We are searching for creative and talented students.
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Application of molecular modelling in the screening and characterization of new solid forms of drug substances
Experimental screening of new solid forms of drug substances, i.e. polymorphs, salts, co-crystals or solvates, is very labor process requiring of testing various conditions. Once the new solid form is discovered it is analyzed by a combination of several techniques including XRD, NMR, Raman spectroscopy, SEM, DSC, solubility and stability. In this project we plan to utilize molecular simulations to support experimental screening procedure. This will increase our fundamental understanding of involved interactions between drug and excipient molecules. In particular, we plan to use molecular modelling in the calculation of the interaction energies of prepared drug solid forms to rank their relative thermodynamic stability and melting temperature. When possible, molecular dynamic simulation will be benchmarked to experimentally measured properties of drug solid forms, i.e. XRD data, or to interactions determined by NMR or FTIR. In the last part, we plan to apply molecular modelling in the description of solubility of newly discovered solid forms in the presence of various excipients (i.e. surfactants, polymers, partner molecules) in water media.
Supervisor prof. Ing. Miroslav Šoóš, Ph.D. (Miroslav.Soos@vscht.cz)
University University of Chemistry and Technology, Department of Chemical Engineering
Parc area Solid state chemistry
Continuous preparation of multicomponent drug solid forms
Screening of new solid forms is typically done in small scale systems including shaken flasks, evaporating systems, ball mills etc., which by design operate in a batch model. Once new solid form is discovered scaling its production is often very complex task. In this project we plan to test capability to use the rotary extruder to prepare multicomponent solid forms of drug substances such as salts, cocrystals or coamorphs. Initially we will use ball mill to prepare new solid forms of selected drug substance. Upon characterization we will upscale of the production process to the application of extrusion, where same form of the drug substance will be prepared in a continuous mode. Detailed investigation of the process parameters will be done to optimize the production process. Both products will be thoroughly characterized including XRD, NMR, Raman spectroscopy, DSC, SEM, particle characterization, measurement of dissolution and stability testing.
Supervisor prof. Ing. Miroslav Šoóš, Ph.D. (Miroslav.Soos@vscht.cz)
University University of Chemistry and echnology, Department of Chemical Engineering
Parc area Solid state chemistry, Preformulation and solid state analysis
On-line measurement and control of continuous pharmaceutical manufacturing
The manufacturing of pharmaceutical products is typically carried out batch-wise. While this makes sense for products that are manufactured only occasionally in small quantities, batch processes also have several drawbacks. These include excessive dead-times, need for cleaning to avoid cross-contamination, and generally poorer control over the product quality. By switching pharmaceutical manufacturing to a continuous mode, equipment utilization can be increased theoretically to 100 %, the footprint of the facilities can be substantially reduced, and standard feed-back and feed-forward control schemes applied. A crucial component of continuous manufacturing processes is the on-line measurement of key quality attributes such as particle size distribution, composition uniformity of granular blends, or moisture content. Advanced analytical instruments such as Near-Infrared probes can be used for this purpose. The aim of this project is to explore the on-line measurement and control methods for continuous pharmaceutical manufacturing in an industrial setting and combine them with computer simulation tools in order to optimize the overall process robustness and operability.
Supervisor prof. Ing. František Štěpánek, Ph.D. (Frantisek.Stepanek@vscht.cz)
University University of Chemistry and Technology, Department of Chemical Engineering
Parc area Preformulation and solid state analysis, Drug design and process
Erosion-controlled drug release from super-placebo tablets
The rate of drug release from a pharmaceutical tablet is one of its most important quality attributes. As an ever-increasing number of Active Pharmaceutical Ingredients (APIs) are developed in alternative solid-state forms such as metastable polymorphs, co-crystals or amorphs, it is desirable to control the rate of drug release by the properties of the tablet matrix rather than by the properties of the API itself. The aim of this project is to explore the so-called “super-placebo” concept, i.e. tablets that erode in a defined way which is independent of the API they contain. The project will systematically explore the relationship between the rate of tablet erosion, the proportion of soluble and insoluble excipients (e.g. mannitol, microcrystalline cellulose), and the manufacturing process parameters (e.g. compaction pressure). The ability to control drug release rate will be demonstrated using several real-world APIs. Advanced instrumental methods such as Magnetic Resonance Imaging, x-ray micro CT and high-speed video-imaging will be used in order to gain a deep understanding of the underlying tablet erosion mechanisms.
Supervisor prof. Ing. František Štěpánek, Ph.D. (Frantisek.Stepanek@vscht.cz)
University University of Chemistry and Technology, Department of Chemical Engineering
Parc area Preformulation and solid state analysis, Drug design and process, Biopharmacy
Flow and compaction properties of pharmaceutical particulate materials and their mechanisms
The topic is focused on the flow, consolidation and compression properties of selected pharmaceutical excipients and their influence by the addition of lubricants/glidants and their mixtures either internally or externally (surface of die). The aim is to optimize composition of tablet mixtures due to the study of surface characteristics and flowability of excipients and their mixtures, and evaluation of compaction process, including force-displacement method and ejection force, as well as the properties of tablets, such as tensile strenght, friability, disintegration, and porosity. Methods: static and dynamic bulk flow properties such as the angle of repose, consolidation dynamic, flow through orifice, avalanching, shear testing (including powder rheology); evaluation of force-displacement, tensile strenght, friability, disintegration, and He pycnometry. Surface properties: BET, AFM, surface energy
Supervisor doc. PharmDr. Zdeňka Šklubalová, Ph.D. (sklubalova@faf.cuni.cz)
University Charles University, Faculty of Pharmacy, Department of Pharmaceutical Technology
Parc area Preformulation and solid state analysis
Process scale-up of pharmaceutical spray drying
Spray drying is a versatile method for converting solutions, suspensions or pastes into dry, free-flowing powders in the pharmaceutical, food and nutraceutical industries. During product development, the formulation and process variables are typically optimised using a laboratory-scale spray dryer, and the process is then transferred to a pilot or full manufacturing scale. However, it is notoriously difficult to maintain the same particle properties using spray dryers at different scales, which often necessitated long and expensive trials to be carried out at the large scale. The aim of this project is to develop a robust methodology for spray drying process scale-up in an industrial pharmaceutical setting. The main focus will on the transferability of particle size and particle morphology, as these two parameters are known to be the most sensitive to parameters that vary between the laboratory and the manufacturing scale spray-dryers: the initial droplet size and the drying conditions (temperature, gas flow rate, and residence time in the drying chamber).
Supervisor prof. Ing. František Štěpánek, Ph.D. (Frantisek.Stepanek@vscht.cz)
University University of Chemistry and Technology, Department of Chemical Engineering
Parc area Drug design and process
Design and application of supra-lipidic structures
The gastro-intestinal transit, emulsification, digestion and absorption of lipidic components from food is crucial not only from the nutritional point of view but also for the dissolution and absorption of many drugs, and therefore their bioavailability. An increasing number of active pharmaceutical ingredients (APIs) that enter the drug development process are highly lipophilic, which makes their bioavailability susceptible to patient-specific dietary habits and often leads to undesired phenomena such as positive food effect. For some APIs, the bioavailability can be up to five times higher when taken on a full stomach compared to bioavailability in the fasted state. The aim of this project is to develop a formulation platform that would make the dissolution, absorption and pharmacokinetics of lipophilic APIs independent of food intake, while not containing a large amount of lipids in the formulation itself. The idea is to create particles that “look like lipids” on the outside but their volume contains predominantly the API or other excipients. Such structures can include e.g. drug suspensions encapsulated in giant liposomes or their aggregates, drug nanocrystals coated by a phospholipid monolayer, or drug-loaded mesoporous silica particles encapsulated within a lipid bi-layer. These elementary structures can also be combined, carrying e.g. several different APIs, functional excipients for absorption enhancement, or pH modifiers that can further reduce patient-to-patient variability.
Supervisor prof. Ing. František Štěpánek, Ph.D. (Frantisek.Stepanek@vscht.cz)
University University of Chemistry and Technology, Department of Chemical Engineering
Parc area Drug design and process
High-throughput development and continuous manufacturing of SMEDD systems
Self micro-emulsifying drug delivery systems (SMEDDS) are formulations that spontaneously form a mini- or micro-emulsion upon contact with water. They typically contain the active pharmaceutical ingredient (API), a mixture of oils or low-melting lipids in which the API is soluble, and one or more surfactants and co-surfactants. SMEDDS are complex ternary or higher-order mixtures whose phase behaviour and properties are notoriously difficult to predict at present. Therefore, the development of SMEDDS is to a large extent an empirical process. Due to a large number of formulation components and their possible ratios, it is rarely possible to completely cover the entire design space, which may lead to sub-optimum formulations or even a false rejection of a particular API as non-formulatable. The aim of this project is to construct a device and develop a methodology for automatic combinatorial screening of SMEDDS formulations and their continuous manufacturing based on the so-called liquid marbles. The project will build on a recently developed patented device called “Marblemat” and extend its capabilities towards combinatorial mixing of formulation components and serial production of liquid marbles with systematically varying composition. Simultaneously, capability for high-throughput testing of the formulation properties such as mechanical strength, temperature stability and dissolution properties will be implemented and demonstrated on several industry-relevant APIs.
Supervisor prof. Ing. František Štěpánek, Ph.D. (Frantisek.Stepanek@vscht.cz)
University University of Chemistry and Technology, Department of Chemical Engineering
Parc area Preformulation and solid state analysis, Drug design and process, Biopharmacy
Application of milling and co-milling processes to formulation of poorly soluble drugs
Poorly soluble drugs (BCS II and IV classes) represent an important segment of marketed drugs. Improving solubility or at least the drug release kinetics is, therefore, a continuing challenge, which is approached by many ways on several levels. The milling, nano-milling, and/or co-milling processes of a drug with optional other excipients provide a way how to change the phase composition of the drug, increase the specific surface of drug particles, modify that surface, and also form composite particles. This study should be aimed at the options and possibilities of improving drug release by all the above mechanisms, especially those related to particle technology. The study should involve both the preparation of particles and their formulation into suitable dosage forms and seek optimized approaches bringing the best performance while complying with the requirements of industrial manufacturability of the formulation.
Supervisor prof. Ing. Petr Zámostný, Ph.D. (Petr.Zamostny@vscht.cz)
University University of Chemistry and Technology, Department of Organic Technology
Parc area Drug design and process
Modeling of drug release from the solid dispersions by diffusion erosion
This work is aimed at the study of the drug release from the solid dosage forms comprising solid dispersions. Such formulations exhibit a well-defined structure, and the drug dissolution can be studied not only by classical dissolution techniques, but also by the apparent intrinsic dissolution. Several fronts develop in dosage forms of this type, where thos fronts corresponds to the liquid penetration, drug leaching and erosion of the residual matrix. Such processes can be described by diffusion-erosion models, which allow determining their rate-controlling steps and characteristic rates to be used for the design of controlled-release drugs.
Supervisor prof. Ing. Petr Zámostný, Ph.D. (Petr.Zamostny@vscht.cz)
University University of Chemistry and Technology, Department of Organic Technology
Parc area Drug design and process, Biopharmacy
Naturally sourced particles for drug delivery
Drug encapsulation into a suitable carrier particle is a common method used in situations where it is possible to either modify the surface properties (e.g. powder flowability or dispersibility in water), to protect the encapsulated component from the environment (e.g. enzymatic digestion in the GI tract) or to control the rate of drug release. Several man-made encapsulation processes are known. However, there are also many natural systems that rely on encapsulation – the cell walls of single cell organisms or their spores, natural particles such as pollen, extra-cellular vesicles, or sub-cellular structures such as vacuoles or other organelles. Some of these structures are highly specific in terms of drug diffusion and its selectivity, or in terms of recognition by cells of the immune system e.g. due to specific shape of the presence of immunomodulatory functional groups on the surface. Yeast glucan particles can serve as a prime example. The aim of this inter-disciplinary project is to investigate the potential of several different types of naturally sourced particles in drug formulation and drug delivery. Both cell-wall derived particles and organelle-based particles will be considered. Special attention will be paid to the process of particle extraction and isolation, as well to the drug encapsulation methodology.
Supervisor prof. Ing. František Štěpánek, Ph.D. (Frantisek.Stepanek@vscht.cz)
University University of Chemistry and Technology, Department of Chemical Engineering
Parc area Drug design and process
Formulation and bioavailability of natural poly-actives
Current paradigm in pharmaceutical drug development and its regulatory environment is based on the concept of Active Pharmaceutical Ingredient (API) as a well-defined single molecular entity that is contained in the dosage form at a precise quantity and chemical purity. Although rational in many ways, this approach is rather different from evolution-proof substances found in Nature. The main drawback is single-API medicines is the development of drug resistance over historically extremely short time periods (only a few decades), which is problematic not only in the area of antibiotics but also in cancer treatment, anti-fungal and various anti-parasitic drugs that gradually lose their effectiveness. In contrast, there are examples of natural systems that maintain their efficacy for many millennia. Perhaps the most prominent example of such material is bee propolis. Chemically, propolis is a mixture of several hundred chemical species with location- and season-dependent composition, which would completely disqualify it as a registered medicinal substance. However, it is exactly this variable multi-component character that makes is so robust and durable, not giving pathogens a chance to develop resistance. Propolis contains both water-soluble and water-insoluble components and is typically applied as ethanol dispersion only for surface treatment. The aim of this project is to explore formulation approaches that could enable oral administration of propolis and ensure its safety and bioavailability. The project is multidisciplinary and will include not only formulation and analytical work, but also in vitro and in vivo testing of biological efficacy.
Supervisor prof. Ing. František Štěpánek, Ph.D. (Frantisek.Stepanek@vscht.cz)
University University of Chemistry and Technology, Department of Chemical Engineering
Parc area Drug design and process, Biopharmacy, Preclinical in vivo testing
CFD simulation of air flow and cross-contamination in production space
One of the severe concerns in the modern pharmaceutical industry is the risk of cross-contamination. Cross-contamination refers to a state where foreign substances get into the manufactured product at a certain production process stage. The most dangerous foreign substances are pharmaceutical compounds present in the production premises during the parallel production of another product. This can be prevented by a suitable space layout with good air exchange. CFD computational tools based on the finite element method (FEM) allow the solution of complex physical problems such as the airflow in enclosed spaces and the study of particle deposition dynamics. The work's subject is the use of CFD to calculate velocity fields and study the deposition of model particles representing dust generated during common operations of the pharmaceutical industry, such as tableting or granulation.
Supervisor prof. Ing. František Štěpánek, Ph.D. (Frantisek.Stepanek@vscht.cz)
University University of Chemistry and Technology, Department of Chemical Engineering
Parc area Drug design and process
CFD modelling and experimental characterization of spray drying process
Low solubility of drugs represent significant drawback in development of new drug products. Possibility to improve this limitation is formulation of drug molecules in amorphous forms, e.g. using hot-melt extrusion, precipitation process or spray drying process. This project will focus on the preparation of amorphous solid forms of drugs using spray drying process. PhD student will be responsible for process modelling using Computational Fluid Dynamic (CFD) and experimental characterization of the process parameters. Developed model will be based on Euler-Lagrangian approach, where gas will be modeled as continuous phase while formed droplets will be tracked as individual entities. Atomization of liquid stream and formation of droplets will be described by combination of VOF-to-DPM approach allowing to model initial formation of droplets followed by their transformation into solid particles. Modelling effort will be combined with the experimental work, where we plan to characterize atomization conditions as well as properties of formed particles. Impact of process parameters, such as gas and liquid flow rates, viscosity of liquid phase, and temperature and relative humidity during spray drying will be considered. In the last stage of the project, gained knowledge will be used to scale up of the process from laboratory scale to pilot scale size.
Supervisor prof. Ing. Miroslav Šoóš, Ph.D. (Miroslav.Soos@vscht.cz)
University University of Chemistry and Technology, Department of Chemical Engineering
Parc area Drug design and process
Assessment of prophylactic and therapeutic potential of various cytoprotective agents in the murine model of multiple sclerosis — experimental autoimmune encephalomyelitis
Multiple sclerosis (MS) is an autoimmune neurological disease characterized by chronic inflammation of the central nervous system (CNS), leading to demyelination and axonal damage, and resulting in a range of physical, mental, or even psychiatric symptoms. Despite remarkable progress in the development of treatment for MS attenuation in recent years, we are still far from finding a curative treatment for MS. Current disease-modifying therapies aim at prevention of inflammatory damage to CNS, but their severe unwanted effects urge for new safe therapeutic approaches. This dissertation will focus on investigation of therapeutic and prophylactic potential of different pharmacological agents in the experimental autoimmune encephalomyelitis (EAE), the most widely used preclinical model for MS. This model is already established in the laboratory of the Institute of Pharmacology. The study will involve testing of potential of different agents (antioxidants, probiotics, prebiotics, synbiotics) to modulate disease severity (by clinical scoring), histological and immunohistochemical analyses of the spinal cords and brains of the mice, measurement of the levels and gene expression of important biomolecules, such as immune parameters (cytokine levels, percentages of the immune cells) and markers of oxidative stress from the spinal cords, spleens and lymphatic nodes of the mice.
Supervisor Mgr. Danica Michaličková, Ph.D. (danica.michalickova@lf1.cuni.cz)
University Charles University, First Faculty of Medicine, Institute of Pharmacology
Parc area Preclinical in-vivo testing
Preclinical in-vivo testing of pharmacokinetics
This research area focuses on development and subsequent utilization of appropriate pre-clinical in vivo models to describe drug pharmacokinetics in vivo. We focus on physiological factors affecting bioavailability and drug fate in the organism as well as determination of pharmacokinetic characteristics of various formulation modifications or alternative ways of drug administration. Broad aim of this research area is to predict formulation-specific pharmacokinetic properties in men based on pre-clinical data
Supervisor PharmDr. Martin Šíma, Ph.D. (martin.sima@lf1.cuni.cz)
University Charles University, First Faculty of Medicine, Institute of Pharmacology
Parc area Preclinical in-vivo testing
Development of inhaled dosage forms and their testing in vitro and in vivo
Viral pneumonia is a disease associated with high mortality. Their treatment requires intensive care and patients with severe course also temporary support of respiratory functions by artificial lung ventilation. From a pharmacological point of view, the treatment of severe viral pneumonia is largely non-specific, although there are some drugs with specific antiviral activity against some pathogens. Because influenza viruses are predominantly respiratory infections, the primary site of replication and excretion of the virus is the airway epithelium. In the case of viral pneumonia, it is the lung epithelium in the lower respiratory tract. Thus, inhaled administration of antiviral agents may represent an elegant alternative to achieving therapeutic doses directly at the site of virus replication. The aim of this study is therefore development of dosage forms suitable for inhaled administration of drugs by nebulization with confirmation of the concept by in vitro and in vivo data. The results will further contribute to a better understanding of the pathophysiology of viral pneumonias associated with pulmonary edema, in which a deterioration in oxygen saturation and in gas exchange is often occurred. In such forms of pneumonia, it is also possible to assume an altered/worsened distribution of drugs and a worsening of the passage of drugs/antivirals from the systemic circulation to the site of their action, i.e. the lung epithelium. Inhaled administration of nebulized drugs in pulmonary pneumonia may therefore represent an advantageous option for their treatment or support for existing treatment.
Supervisor prof. MUDr. Ondřej Slanař, Ph.D. (ondrej.slanar@lf1.cuni.cz)
University Charles University, First Faculty of Medicine, Institute of Pharmacology
Parc area Preclinical in-vivo testing
March 11. 2021