Microinnova has performed different halogenation reactions in the lab and has gained significant experience. For example, halogenation of aromatic systems with elemental halogens (fluorine, chlorine, bromine, iodine) or hydrohalogenation with hydro-halides has been carried out. “Flow process design and scale-up for safe and selective halogenation is a core competence of Microinnova.” says Dirk Kirschneck, Strategic Director of Microinnova.

Hydro-halogenations of double bonds and epoxides were realized with hydrogen-halides, as well as halo-exchange reactions. By mixing chloro-aliphatic and chloro-aromatic substances with HF-complexes, fluorinated products were obtained. Pressurized reactors operating at high temperatures were used for performing halo-exchange; continuously operating systems are one of the safest methods of manufacturing chemicals. For the safe handling of halogens at lab scale, chlorine and bromine generators were used to provide a steady supply of the toxic reagents. Highly reactive reagents such as sodium hypochlorite can be formed in-situ using flow technology and offer easier handling and storage. When combined with inline purification, they can be used consecutively as reagents for the desired chemistry. By providing stochiometric ratios of the reagents, high selectivity can be achieved e.g. for the selective oxidation of secondary alcohols in the presence of primary alcohols.

Photohalogenations, as well as oxidation reactions, were carried out with the supplied reagents. Such generators could also be realized at pilot and small production scale, in order to avoid storage of the toxic reagents. Such generator approaches could also be realized for even more dangerous substances such as halo-azides and halo-cyanides. Microinnova can assist and provide such generator systems.

Trials at pilot stage have been successfully performed with elemental fluorine and with elemental bromine in Corning reactor systems. In the future, both pilot trials may be realized at production scale.

Contact our expert team to learn more about our competence in halogenation and our other services!

CordenPharma Chenôve SAS has commissioned a continuously operating modular API and intermediates synthesis plant that they recently put into operation to realize the benefits of process intensification. It consists of two feed modules with two dosing lines each, and four dosing lines altogether. Two of those dosing lines are made of Hastelloy, one is made of stainless steel and the other dosing line is free of metal. Each dosing line is designed for a flow between 15 and 250 ml per minute at 20 bar.

Furthermore, there is one reaction module and a quench module, both of which can supply a maximum of 500 ml per minute at 20 bar. The four thermostats enable the use of different temperature levels in different stages of the process. The plant can operate with liquids, gases, and suspensions as feed streams, and it can be used with various continuous reactor technologies while operating automatically.

Our modular design provides smart process flexibility enabled by a standardized and uniform exchange of functionalities for multi-purpose processes and mobile installation in a smart manufacturing environment based on walk-in fume hoods. Achieving full customer satisfaction, Microinnova’s engineers are delighted to have been able to once again provide more flexibility and increased capacity to a valued client.

Based on nearly 20 years in the field of flow process design the team at Microinnova has executed more than 200 projects in flow chemistry. Different types of polymerization reactions have been executed including free-radical and ionic polymerizations, as well as polyester and oligomer synthesis. We address product quality and safety issues since these types of exothermic reactions benefit from a large heat transfer efficiency and excellent mixing.

Their large exothermicity is of significant safety concern. Uniform processing conditions have a huge impact on the quality of the material such as molecular mass distribution. Projects with polymers have been executed for end-capping, exchange of functional groups, and cross-linking, for example. Radical starting materials, as well as urethane and dicarboxylic monomers have been synthesized. The continuous reaction of back-bone structures used in formulations (e.g., gel structures) improves the level of product quality in addition to the interfacial area. Microinnova has experience in handling materials with viscosities of up to 100,000 mPas. Polymer processes benefit from a specific cooling surface of up to 200 m²/m³ with a high k-value and narrow residence time distribution.

…by kicking off the Project “PharmComplete” using Digital Twin, Model-Predictive-Control and PAT strategies.

A shift towards more efficient and controlled processes is taking place in the pharmaceutical industry with process analytical technologies, continuous manufacturing and advanced process control strategies being central elements. While different suppliers make plug and play lines available, especially in the field of solid dosage manufacturing, the change to completely monitored and automated processes is being implemented only slowly. Process data is still mainly used for manual operation decisions and out-of-specification product is discharged. Model-based predictive control is rarely applied in an industrial environment. Labor-intensive quality control, variable product quality and inefficient utilization of resources is common.

PharmComplete’s goal is to develop a digital twin for an integrated pharmaceutical manufacturing line, from API synthesis to downstream processing. Process models will be developed for all unit operations or pre-existing models will be adapted to the specific conditions and materials. With a machine learning approach, a focus will be on model simplification for easier utilization in an industrial environment. The digital twin enables the execution of process simulation and control. Intelligent process control based on process information generated from real-time process data enables robust processing, reduction of waste and constant high product quality assured during the production campaign. RCPE with TU Graz, University of Graz, evon GmbH and Microinnova Engineering GmbH are working closely together on building new routes for digital processing and Industry 4.0. 

We were honored to have the opportunity to sponsor the 2021 EFCE Excellence Award in Process Intensification! The recipient of this award was Dr. Evangelos Delikonstantis whose Ph.D. work, titled “Plasma-Assisted Non-Oxidative Methane Coupling to Olefins”, looked into how methane can be converted to ethylene using a nanosecond pulsed plasma. Dr. Kirschneck, who presented the award, and Dr. van Gerven, who is the chairman of the working party “Process Intensification”, were very interested in Dr. Delikonstantis’ subsequent presentation. He noted that beyond the non-oxidative methane coupling to ethylene, the findings demonstrate the potential of nanosecond pulsed plasma for catalysis and should pave the way to other important chemical conversion reactions. If powered by renewable electricity, the process could pave the way for novel low-carbon ethylene production processes, with an estimated carbon footprint of 1.3kg of CO₂-equivalent per kilogram of ethylene.  

More infos on this outstanding work in this press release.

BACKGROUND

O₂-dependent biotransformation reactions have proven difficult in fine chemical manufacturing due to the mass transfer limitations of supplying O₂ to the enzymatic reaction, hence affecting the level of efficiency achieved. Previous research has shown that enzymatic processes involving gases have a high potential for process intensification by implementing continuous flow processing technology.

TECHNOLOGY

In a cooperation between acib and Microinnova Engineering GmbH, with more than 15 years of experience in flow chemistry it has been proven that process intensification can be applied using continuous flow processing. This technology offers a comprehensive solution with a pressurized system that results in a significantly higher level of dissolved oxygen. A continuous flow reactor pressurized to 34 bar enables biotransformation to be conducted in a single liquid phase and significant increase of enzymatic activity was detected already at 10 bar. For glucose oxidase, the intensification factor for enzyme activity was up to 2.5 and amino acid oxidase showed an intensification factor up to 6 for the enzyme activity. High product concentration has been demonstrated with the concentration being 6 to 10 times higher at 34 bars compared to atmospheric pressure. See also Bolivar J.M., Mannsberger A., Thomsen M.S, Tekautz G., Nidetzky B. (2019) Biotechnology and Bioengineering, 116(3), 503–514.

Find out more in this acib newsletter!

Corning Incorporated and Microinnova recently celebrated the opening of the Corning® Advanced-Flow™ Reactors (AFR) Application Qualified Lab (AQL) at their facility near Graz. Application qualified labs enable AFR customers to effectively access continuous-flow demonstrations, experimental trials, feasibility testing, and chemical reaction process development.

Corning currently has one other AQL in Europe at the University of Liège, which opened in 2017, as well as several operational AQLs worldwide that support the business. These regional facilities provide customers with convenient access to AFR Technology.

Microinnova is an innovation-based company focused on process development, design, and the realization of continuous pilot lines and manufacturing plants. Based on their critical parameter approach, Microinnova intensifies synthesis, as well as work-up and formulation processes using a wide range of different technologies leading to high-performance processes.

Microinnova has recently established a fluorine lab at their facility in Graz and are utilizing Corning’s G1 Silicon Carbide (G1 SiC) reactors to process highly toxic and corrosive chemicals in an inherently safer, more efficient way that can help customers in pharmaceutical, fine and specialty chemicals industries create a better end product.

“We’ve worked closely with Microinnova over the last few years, and the core values of innovation and commitment to inherently safer continuous flow chemistry really makes this collaboration a great fit for both companies,” said Alessandra Vizza, regional business director, Corning® Advanced-Flow Reactors. “Corning’s equipment and materials enable more stable reactions and can reduce inherent risks associated with handling/processing hazardous chemicals – which is really what the core of AFR Technology is all about.”

The location of this laboratory will help Microinnova provide broader reach to their customer base within the pharmaceutical, fine and specialty chemicals industries in Europe.

“We operate to strengthen our capabilities in the fields of fast, exothermic or highly corrosive processes for development as well as for manufacturing plant realization as a system integrator,” said Dr. Dirk Kirschneck, strategic director, Microinnova. “Based on the strong collaboration between the two companies since 2007, we are looking forward to continuing to work with Corning on future programs as one of their Application Qualified Labs.”

In addition to its AQLs, a critical part of the AFR business’ model for more than a decade has been its commitment to educating the regions where it operates.

“In Europe, we’re actively trying to educate both at the academic and industrial level on the value of continuous flow technology,” Alessandra said. “We’re hopeful that our broad product offerings as well as collaborations with companies like Microinnova will help us in this effort.”

We expect that speed and flexibility will be success factors for chemical businesses in the future. The example of Ryan Air illustrates the importance of focusing on value generation for the customers and how innovation in a business model can achieve it.

Modular plants offer the best processing solution giving both flexibility and speed; ownership may not be key in the future. To facilitate this, design modification between the modules and within the modules should be enabled with other aspects considered such as engineered spaces and access for maintenance and modifications. Module Type Package (MTP), a technology offered by Microinnova, enables a Plug-and-Play solution for processing plants (like USB for computers). It is important to also consider the changeover possibilities, physical movement and how the infrastructure is designed so that the equipment fits the process. Furthermore, we also supply plant virtualization where we engage in the pre-testing of process conditions using digital twins/model predictive control, documentation of modifications with an implemented as-built/modified documentation, PAT and pre-HAZOP scenarios. Moreover, we expect that some plants will consist mainly of pre-designed and pre-built package units in the future with a predicted 60-80% of the modules being pre-designed. An exception to this being specific reactors addressing a certain set of critical parameters that are designed bespoke for an individual process. A similar shift has been observed in the automotive industry, where cars are designed based on a platform concept. 

Learn more about how your chemical business can benefit from modular plants! »

Space economy is a typical issue for debottlenecking batch projects. Since a continuous approach reduces mass and heat transfer distances up to a factor of 100, these solutions can easily be integrated into an existing batch environment. A number of different strategies can reduce or replace batch processing times. For example, a batch processing step can be translated into a continuous plant skid. 

In some cases, the mixing operation or even the reaction itself can be executed while filling the reactor. Reagents, especially hazardous ones, can be synthesized in situ. Large savings can be achieved in the field of acid-base-reactions, since they are characterized by a strong heat release. These kinds of processes can reduce residence times from hours to minutes, since they are limited by the heat exchange which can easily be controlled in a continuous device. Mobility of skids enables a flexible use in connection with different plants. Optimizing mass and heat transfer is an important factor in reducing the costs per kilogram, leading to an increased competitiveness.

Find out more about our debottlenecking capabilities!

The benefits of smart continuous manufacturing and process intensification are much broader than previously expected. Through our trusted approach, Microinnova gives the chemistry what the chemistry needs by identifying the critical parameters for each process. By selecting the best technology via process intensification and the application of continuous flow technology, we enable one or more of the following advantages: higher yields, higher selectivity, reduction of operation steps, increased labor efficiency, higher safety, increased development speed, energy savings and more.

Chemical reactions which are tricky to handle, e.g. highly exothermic or toxic reactions become less of a threat and/or will be much easier to process in a robust and efficient manner. Also, mixing-sensitive reactions profit from a continuous approach and will perform much better than in a traditional batch process. Debottlenecking projects have demonstrated that continuous manufacturing could be effectively used to double capacity. In order to increase the visibility of the vast benefits of smart continuous manufacturing and process intensification, we have compiled a list of some of the plants we have designed and built for our customers. Even though processes are rather different, each solution generates a significant value for our customers. 

Take a look at our selection of Case Studies!