Author: cespe

Currently the Laboratory of General Biochemistry & Physical Pharmacy houses 4 closely collaborating research groups: the Biophotonic Research Group, the Ocular Delivery Group, the Lung Delivery Group and the Vaccine Delivery Group. The global research focus of our teams is on the delivery of bio-therapeutics, especially nucleic acids. Our teams offer a multifaceted portfolio of competencies including pharmacology, material knowledge and expertise in drug delivery, nanotechnology, cell biology, immunology, biophysics, optics and bio-photonics.

• Biophotonics Research Group: Research of this team is as aimed at the development of biophotonics-based technologies to (i) study the biophysical behavior of nanomedicines in cells and tissues and (ii) enable more efficient drug delivery. With regard to the former, the Biophotonics Research Team has specialized in the development of advanced light microscopy methods and their application to study the interaction of nanomedicines with biological barriers.
• Ocular Delivery Group: This group is highly experienced in developing (and using) in vitro, ex vivo and in vivo models for the evaluation of non-viral nucleic acid delivery to the retina. This team recently developed an ex vivo retinal explant from bovine eyes which keeps the vitreous and inner limiting membrane (ILM) intact during dissection. This allows to evaluate the potential of intravitreally injected nanoparticles to deliver therapeutics to the retina.
• Lung Delivery Group: The Lung Delivery Group mainly focuses on exploring novel ‘bio-inspired’ approaches for the delivery of nucleic acids. A major aim of this team is to develop innovative strategies to stimulate cytosolic delivery of nucleic acids in lung-related target cells for the treatment of pulmonary pathologies with a clear unmet medical need, including obstructive lung diseases and respiratory infections. To reach this goal, the team focuses on (i) exploiting endogenous materials for drug delivery, such as pulmonary surfactant, (ii) repurposing of small molecular drugs as adjuvants to promote nucleic acid delivery and (iii) improving nanomedicine design for in vivo use.
• Vaccine Delivery Group: Research projects of the Vaccine Delivery Group are situated at the interface of drug delivery and immunology. As such, we explore the potential of nanotechnology or physical approaches (ultrasound) to manipulate the immune system.

The Laboratory of Pharmaceutical Process Analytical Technology (LPPAT) focuses on the implementation of PAT systems in innovative pharmaceutical production processes and therefore has always worked in close collaboration with the Laboratory of Pharmaceutical Technology of Prof. Dr. C. Vervaet and is part of the QbD and PAT Sciences Network. 

Manufacturing processes of interest:

• Freeze-drying
• Continuous wet granulation
• Production of solid oral dosage forms
• Continuous melt granulation

Implementation of PAT systems:

• The development and implementation of process analyzers in the process stream allowing real-time collection of critical process and (intermediate) product information.
• Data-analysis methods (chemometrics) allowing to extract useful information from the large datasets that process analyzers supply. Process analyzers are only valuable if they provide the desired information with sufficient accuracy. Being able to build accurate and robust models to reliably translate the data (e.g., obtained spectra) into process or product knowledge is crucial.
• Design of Experiments (DoE) to maximize the information content from experimental series while keeping the number of experiments low. As the process (step) endpoints and the intermediate or end product properties (e.g., product solid state, chemical properties, physical properties,…) are influenced by numerous process and formulation variables, appropriate experimental design approaches must be applied to find out which variables and variable interactions significantly influence processes and product properties.
• Statistical process control and visualization: a final aim of implementing PAT systems in pharmaceutical production processes is complete process control. Based on process knowledge and process models, the information obtained in real-time should be used for guiding the process to its desired state, possibly allowing real-time release. Early warnings should be given when a process is moving into an unwanted direction and the process models should allow to determine how process settings must be adapted by operators to lead the process to its desired state, thereby reducing batch rejection.
• Mechanistic modelling: empirical modelling is based on historical data and as such they are of limited use in new applications outside the experimental space studied. Apart from cause-and-effect between variables, not much else is required in terms of process knowledge. Mechanistic modelling is based on the fundamental understanding of the underlying physics and chemistry governing the behaviour of the process. Hence, mechanistic modelling does not require much data for model development, and hence is not subject to the idiosyncrasies in data. Mechanistic modelling forces to fundamentally and completely understand processes. The different steps of mechanistic modelling are mentioned in appendix. This new approach of modelling of pharmaceutical processes should allow making useful process simulations and process predictions.

The research at the Laboratory of Pharmaceutical Technology (Ghent University) focuses on the development of innovative drug dosage forms (mainly solid dosage forms) for human application as well as for veterinary use. These dosage forms are based on pharmaceutical accepted excipients used as such or as mixtures to impart specific drug release properties (immediate, controlled or sustained release) to the formulation. The lab has a strong research focus on continuous manufacturing techniques.

The projects at the Laboratory of Pharmaceutical Technology are focused on the following topics:

• Granulation: Current research mainly focusses on process and formulation development for twin screw wet and melt granulation as well as their downstream processes. Therefore, evaluating the interplay between raw material properties and process settings is of high interest. This approach is used to (i) derive preferred excipients platforms for novel APIs, (ii), evaluate the impact of batch-to-batch variability and (iii) evaluate the applicability of botch conventional and non-conventional excipients for continuous processing.
• Tabletting: Ongoing work investigates the influence of raw material and blend properties on the die-filling and tabletability during continuous manufacturing. Residence time distributions in the feedframe and influence of different process parameters are being studied. In addition, the influence of feeding and blending during continuous direct compression on the tablet content uniformity is evaluated.
• Compaction simulation: Currently, our team is working on the evaluation of the external lubrication system on the compaction simulator (Styl’One Evolution). In addition, the correlation between the tableting process and tablet quality of tablets produced on the Styl’One Evolution tableting instrument and Modul™ P rotary tablet press is studied.
• Hot-melt extrusion and 3D-printing: Hot melt extrusion is used for designing sustained release dosage forms using conventional and non-conventional polymeric materials for controlled drug release. On the other hand, the extrusion process is used to enhance the bioavailability of poorly soluble drugs by preparing molecular dispersions for immediate release dosage forms. The development of personalized 3D dosage forms with versatile release profiles is also one of our research interests. Recently, FDM 3D printing was used as an alternative HME downstream processing technique to produce personalised medicines for the manufacturing of high drug loaded dosage forms, hence offering a lot of formulation freedom for the on-demand production of personalized dosage forms at the point-of-care.
• Spray-drying: Research on the spray dryers is focussed on formulation of particles for dry powder inhalation, co-processing to obtain particles with the desired properties (e.g. improved compressibility, flowability) and creation of micro-particles for oral antigen delivery.
• Freeze-drying: Our lab developed a continuous freeze-drying process in collaboration with the Laboratory of Pharmaceutical Process Analytical Technology. This continuous freeze-drying concept is based on spinning the vials during freezing (I.e. spin-freezing) and on non-contact energy transfer via infrared radiation during drying. This improves process efficiency and product uniformity compared to conventional batch drying. Our research focus is development of a formulation strategy and optimisation of the models used in the different steps of continuous freeze-drying.

The research of the Supramolecular Chemistry Group (Ghent University) focuses on the molecular design of polymer materials for a broad range of applications, including drug delivery, biomaterials and excipients. The group has a strong expertise in the synthesis of defined (functional) polymer structures with a special emphasis on poly(2-oxazoline)s, responsive polymers and supramolecular materials.

Some illustrative examples of relevant projects are listed below:

• Poly(2-oxazoline) matrix excipients for oral dosage forms enabling high drug loading (up to 70%-80) amorphous solid dispersions of poorly water-soluble drugs, such as flubendazole, mebendazole and fenofibrate
• Poly(2-oxazoline) matrix excipients for oral dosage forms enabling high drug loading (up to 70%) sustained release formulations of drugs with good water solubility, such as metoprolol tartrate and metformin
• Cationic polymers for transfection of pDNA, siRNA, mRNA and saRNA enabling better in vitro transfection than lipofectamine and similar in vivo transfection as lipid nanoparticles
• Polymer-drug conjugates to reduce systemic toxicity and enhance blood circulation time, possibly in combination with targeting ligands, including antibody-drug conjugates
• Polymer-protein conjugates to enhance blood circulation time and enhance protein stability
• Responsive polymers that are insoluble in the blood stream but rapidly solubilize upon cell internalization, through either protonation or degradation of side chains under mild acidic conditions

The Synthesis, Bioresources and Bioorganic Chemistry (SynBioC) Research Group is active in the broad field of organic synthesis with projects ranging from the synthesis of new bioactive compounds for applications in the medicinal and the agrochemical field, the isolation and study of natural products, the use and chemical modification of renewable resources, to the implementation of green chemistry, microreactor technology and photo chemistry.

Within the framework of organic and bioorganic chemistry, the following research lines are elaborated:

• The chemistry of small-ring azaheterocycles: This research involves the study of regio- and stereoselective ring transformations of constrained (phosphonylated) azaheterocycles such as aziridines, azetidines and beta-lactams. Next to the fundamental aspect of designing and evaluating new synthetic methods, the application of these techniques is also employed for the construction of a broad variety of heterocyclic target compounds with biological interest (diversity-oriented approach).
• Synthesis of bioactive substances: Several projects are focused on the synthesis of specific classes of natural product analogues (e.g. curcuminoids, quorum sensing signaling compounds) and other new compounds associated with certain biological activities (target-directed approach). Examples include the synthesis of anticancer agents, antibiotics, antimalarials, analgetics, HDAC-inhibitors, crop protection products,…
• Green chemistry and renewable resources: Renewable chemicals and materials are currently a hot topic in research and industry. The depletion of fossil resources and the exhaust of greenhouse gases force us to think about alternative sources for the chemical industry and the energy sector..Our research group focuses on the modification of non-fossil resources towards renewable chemicals, such as the modicification of biopolymers (inulin, chitosan), the use of 10-undecenoic acid (derived from castor oil) and the production of biofuels and renewable fuel additives.
• Microreactor technology: Microreactor technology (MRT) provides a number of specific advantages compared to batch processes: it is often more selective and efficient, has a better mass and heat transfer capacity, consumes often less reagents and solvents, has good safety features and allows to work with very reactive and/or toxic reagents. The SynBioC research group is active in the application of microreactor technology for multicomponent reactions, reactions using dangerous reagents, fotochemical and low temperature reactions.