Process technologies for active compounds

The pharmaceutical industry is continuously searching for new molecules for pharmaceutical applications as well as improved manufacturing and downstream processing techniques. The focus of this working group is therefore on the chemical synthesis of active pharmaceutical substances as well as their purification and the technical implementation of associated processes. A major goal is to convert processes that were previously operated batchwise into a continuous operation mode.

At the ICTV, we are working on various projects in the field of biotechnology and pharmaceuticals, where basic process engineering operations are used to obtain or purify products. For example, the development of a rotating reactor serves as an apparatus for crystallization processes with low shear. Another research approach is the use of novel sensor systems for process monitoring and their integration into intelligent and self-learning control structures, for example on the basis of machine learning approaches.

Current projects

Adsorption and chromatography are particularly well suited as separation or purification processes when the valuable substance or impurity is present in a complex mixture or in low concentrations. Furthermore, the processing of temperature-sensitive products such as natural products is advantageous, as adsorption is preferably carried out at low process temperatures. In industry, there are a variety of applications ranging from wastewater treatment to biotechnological production of pharmaceuticals. Recently, especially the use in the liquid phase is of increasing interest, e.g. in the purification of sugars from lignocellulose streams or in the reaction-integrated adsorption of so-called rare sugars. Knowledge of isothermal data is a prerequisite for all these processes in order to first select a suitable adsorbent for the process task and then to properly design the overall process. In the liquid phase, the focus is on the experimental determination of equilibrium data and the question regularly arises as to which methods should ideally be used to investigate the respective system with regard to the problem to be investigated. The determination of adsorption equilibria can be carried out quickly and in a material-saving manner using so-called dynamic methods.
The research project focuses in particular on the isotherm determination of adsorbents that were not developed for chromatographic applications. Especially in dynamic experiments in self-packed columns, this leads to a comparatively high axial dispersion and thus to low theoretical separation efficiencies. Since these methods were only used for chromatographic systems for a long time, there is a need for further research on the suitability with different substance systems as well as on the selection of suitable process conditions and the existing measurement uncertainties before a broad application of these useful methods can be expected.

The development of novel devices is an essential part of process optimization in the pharmaceutical industry. The Archimedes Screw Crystallizer / Reactor (ASKR) is an example of such a device, which was developed for the continuous processing of heterogeneous systems, e.g. particle suspensions. The overall rotation of the reactor jacket causes a mixing and conveying effect that moves the individual partial volumes through the reactor, subdivided by an internal helix. This mechanism promises advantageous residence time behaviour of the conveyed fluid elements and strives for a superior gentle mixing ensured by avoiding agitators. Such a low-stress mixing effect is highly important for shear-sensitive systems, since enzymes or cell cultures can be damaged by high hydromechanical stresses and fragile crystals can exhibit undesirable abrasion. In addition to the continuous process platform of the ASKR, the Rotating Disc Reactor (RDR) has been developed as a batchwise alternative. It acts as a reactor for extremely high-value products with very small batch volumes or as a screening tool for the ASKR. Thus, due to improved metrological accessibility in the RDR, flow and mixing characteristics become observable and process-specific optimization can be carried out as well as transferred to the ASKR. One major focus is the integration of crystallization processes for active pharmaceutical ingredients, because these processes have a high potential for optimization and can benefit in particular from the features of the ASKR and RDR.

Crystallization represents a central process in many pharmaceutical production processes. Used as purification, separation or purification of active ingredients, the process has a significant impact on product quality there. Also, process steps further downstream can depend on the properties of the crystals. Accordingly, there is a great interest in process control systems that can ensure a consistent and specific quality of the crystal properties in the process. In addition, in most cases the process is very energy-intensive. Thus, there is great interest in ways to save energy, especially in view of the current climate and energy situation.

Among process control strategies, especially model-based ones can be optimized very efficiently. Their main disadvantage is, that the creation of a mathematical model to describe the process is often time-consuming and very complex due to the nonlinear interrelationships of process variables.

Therefore, the ICTV is researching possibilities to improve conventional, model-based process control by using machine learning techniques. For example, neural networks are trained with process data in order to make predictions about the further course of the process instead of a conventional model and thus serve as a basis for control.

Research projects finished during the last 5 years

Promising candidates for API or drug development tools, such as protein kinase inhibitors or organometallic complexes with N-heterocyclic carbene ligands (M-NHCs), frequently exhibit poor water solubility. This gives rise to challenging tasks in synthesis, reaction monitoring, process control and scale-up of these manufacturing processes. This project aims at the establishment of a continuous synthesis and downstream processing of poorly water soluble species with special emphasis on the reaction stage. Reactor design and characterization together with reaction monitoring and modeling shall enable continuous manufacturing of API at high and constant quality. It also provides the basis for a reliable process as well as equipment scale-up to larger quantities. Energy intensification measures, such as ultrasonication or microwaves, shall be tested for potentially beneficial applications. Close interactions with groups focusing on chemical and molecular aspects, solvent selection as well as modeling are essential.

Carbohydrates account for the largest amount of biomass on earth and could be a cheap source for the production of fine chemicals, drugs or dietary supplement. The aim of this project is the conversion of the bulk sugar sucrose into the expensive disaccharide laminaribiose using a trienzymatic system. An in-situ product recovery via adsorption is carried out directly in the bioreactor to improve the process in terms of cost-efficiency and effectivity. Therefore, synthetic BEA zeolites are used, since they are known for their good adsorption abilities in systems containing sugar. However, the best adsorbate in terms of capacity, selectivity, kinetics and desorption properties has to be chosen from the huge selection of commercial available zeolites. The three enzymes needed have to be immobilized and entrapped in biopolymers. The chemical (diffusion and distribution) and mechanical (stability) properties have to be determined and optimized. Moreover, the kinetic properties of the immobilized enzymes have to be determined. These data are used to transfer the isolated conversion steps into a complete system. This system may also be modelled and optimized. In the end, a pilot plant is planned to produce larger amounts of laminaribiose and conclude general design rules for trienzymatic systems.

Funded by: Federal Ministry for Economic Affairs and Energy (BMWi)
Project Management: Central Innovation Programme for small and medium-sized enterprises (SMEs)
Project ID: ZF4307806ST8
Time: 1.7.2018 – 30.9.2020
Contact: Conrad Meyer

Crystallizations are crucial in many industrial processes. Examples are the purification of active pharmaceutical ingredients (APIs) in the pharmaceutical industry or the production of sugar in the food industry. Crystallizations are complex and product properties depend on many process parameters, e.g. temperature, mixing or impurities. To be able to guarantee a steady product quality, exact knowledge of those properties during the whole process is necessary. Therefore, the goal of this project is to develop a new sensor system to monitor the crystallization progress. Through the combination of several measuring techniques in one system, the project aims to make a broad understanding of process factors during the process possible. Not only the continuous, but also the disperse phase is to be considered simultaneously. The focus at the Institute for Chemical and Thermal Process Engineering is the testing of sensor prototypes in a lab-scale crystallizer in collaboration with partners from industry and university. The final goal is to allow for an optimal process control.

Promising API are often poorly soluble in water, which causes difficulties in the design of adequate synthesis and purification processes. An example for such poorly soluble API are Alkynyl Phosphine Gold(I) Complexes which exhibit excellent inhibition towards the enzyme Thyoredoxin reductase (TrxR) making it a promising anticancer drug.

Starting from the lab synthesis suitable process steps shall be identified and optimized for the production of these Alkynyl Phosphine Gold(I) Complexes. A model based evaluation of the experimental results leads to the design of a continuous process which is then validated experimentally to provide data for further scale-up.

Process analytics ensure constant product quality throughout the transition from lab synthesis to mini plant. The synergy of mini plat processing, analytics as well modelling leads to the development of energy- and mass balance and provides data necessary for further scale up and design of tailored reaction and purification devices.

The main goal is to transfer lab syntheses of promising poorly soluble model active pharmaceutical ingredients (API) from various pharmaceutical research areas (cancer research, antibiotics, …) to a continuous manufacturing and technical scale.
Based on this transfer, a concept for a continuous system has to be developed which can handle various synthesis and isolation processes for any kind of poorly soluble API in a modular based structure.
In order to develop this concept, the research project deals with the lab synthesis of 4,5,6,7-Tetrabromo-2-(1H-imidazol-2yl)isoindolin-1,3-dion (TBID), a protein kinase (researched at the Institute for Medical and Pharmaceutical Chemistry (IMPC)), whose high selectivity and strong inhibition on the enzyme HIPK2 (involved in cancer genesis) has been shown.
To reach the goal of a continuous modular based process concept, the lab synthesis from the IMPC is firstly transferred to a scalable synthesis and isolation of the product. Using (online) process analytic technology (PAT) like FBRM, FTIR or HPLC, synthesis and isolation are optimized, process parameters are characterized (kinetics, …) and finally milli/micro structured components required for continuous synthesis and isolation are realized.
The gained process knowledge is then combined to construct a mini-plant with consistent heat-/mass transfer for continuous synthesis and isolation of TBID on a scalable base.

Process technologies for active compounds

Current projects

Research projects finished during the last 5 years

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