Periodic Reporting for period 1 - PharmaCrystEng (Development of novel rapid design methods for separation of enantiomers by crystallization: a process systems engineering approach)
Berichtszeitraum: 2021-06-01 bis 2023-05-31
The Action “Development of novel rapid design methods for separation of enantiomers by crystallization: a process systems engineering approach” looks at how process systems engineering can be exploited to obtain enantio-pure crystals in desired particle size effectively and safely. The enantio-purity became a critical pharmaceutical issue after the Thalidomide crisis, when one enantiomer of the molecule delivered the desired physiological effect, whereas the counter-enantiomer caused severe birth defects, impacting tens of thousands of pregnancies. The size of particles matters because different particle sizes dissolve at different rates (think of the powder and crystalline sugar). This is a critical property of drug products: during a heart attack, one wants immediate, short-term effects, but after a dentist’s visit, one may choose to take a painkiller that will last for hours.
There are numerous techniques to obtain enantiopure products, which can be divided into two major groups: stereoselective synthesis, in other words, choosing chemical reactions that will selectively produce the desired enantiomer, or separate enantiomers from their mixtures. Separations are usually realized by diastereomer salt formation, crystallization, and chromatography. The particle size can be adjusted in the crystallization, and secondary correction operations such as granulation or milling can also be employed. This research aimed to combine the separation of the enantiomers with controlled particle formation innovatively and effectively, which cuts costs, shortens manufacturing technology and improves overall safety. This is important as solving the issues can bring affordable medicines closer to us and those in need. This project targets a class of materials, so-called conglomerates, which has the property that enantiopure crystals are being formed. Crystallizing selectively one or the other enantiomer is called preferential crystallization (PC). This project looks at how PC can be optimized and designed rapidly, with minimal or without preliminary information about the crystallization behavior of the compound of interest.
The formal objectives of this Marie Skłodowska Curie Action (MSCA) have been to (a) apply crystallization systems engineering to enhance the preferential crystallization of enantiomers; (b) develop detailed population balance-based process models for PC in batch and continuous mode and apply multi-objective optimizations to find the best operating conditions and (c) apply data mining and machine learning on the simulated data to obtain shortcut design methods. A parallel goal of the MSCA Individual Fellowship is to foster the development of the individual researcher and support the integration into the local academic system.
There are numerous techniques to obtain enantiopure products, which can be divided into two major groups: stereoselective synthesis, in other words, choosing chemical reactions that will selectively produce the desired enantiomer, or separate enantiomers from their mixtures. Separations are usually realized by diastereomer salt formation, crystallization, and chromatography. The particle size can be adjusted in the crystallization, and secondary correction operations such as granulation or milling can also be employed. This research aimed to combine the separation of the enantiomers with controlled particle formation innovatively and effectively, which cuts costs, shortens manufacturing technology and improves overall safety. This is important as solving the issues can bring affordable medicines closer to us and those in need. This project targets a class of materials, so-called conglomerates, which has the property that enantiopure crystals are being formed. Crystallizing selectively one or the other enantiomer is called preferential crystallization (PC). This project looks at how PC can be optimized and designed rapidly, with minimal or without preliminary information about the crystallization behavior of the compound of interest.
The formal objectives of this Marie Skłodowska Curie Action (MSCA) have been to (a) apply crystallization systems engineering to enhance the preferential crystallization of enantiomers; (b) develop detailed population balance-based process models for PC in batch and continuous mode and apply multi-objective optimizations to find the best operating conditions and (c) apply data mining and machine learning on the simulated data to obtain shortcut design methods. A parallel goal of the MSCA Individual Fellowship is to foster the development of the individual researcher and support the integration into the local academic system.
The objectives and goals have been addressed via four specific work packages: (1) direct design development for PC processes, which included a significant experimental part and a simulation study, leading to an accepted and submitted manuscript (2) Population balance-based PC process model development and multi-objective optimization, which created a flexible and highly performant crystallization simulation. This flexible solver was deployed for parametric multi-objective optimizations, which resulted in a database of optimal operations obtained at different process parameters (that is, what a plant operator can decide) and kinetic behaviors (that represent different crystallization systems); (3) Shortcut design method based on the outcomes of WP2 and its experimental validation, which covered the application of data-science on the database of optimal solutions generated in the WP2, with novel discoveries. A journal publication was accepted from the results of this WP, and the data will be used further for subsequent research; (4) Communication & dissemination. Besides these work packages, the transfer of knowledge was also enunciated in the application, which included communication to industrial stakeholders and the broad public audience. The project’s overall objectives have been met. The (re)integration was successful as the Research Fellow joined the host institution as an associate professor right after the MSCA ended, which was enabled by this fellowship.
Results of this MSCA are reported in two accepted papers, two submitted manuscripts, and four papers born from the bidirectional transfer of knowledge with the hosting research group. The results were published at national and international conferences. A popular science paper was also published in the leading Hungarian journal (Élet és Tudomány/Life and Science). Furthermore, the manuscript of the second edition of the Advanced Process Engineering Control book was finalized, with the anticipated publication date of November 2023 at DeGruyter. The simulators and the data sets generated during this MSCA will inform and enhance dozens of publications in the coming years, in addition to the ones produced and published during the fellowship itself.
Results of this MSCA are reported in two accepted papers, two submitted manuscripts, and four papers born from the bidirectional transfer of knowledge with the hosting research group. The results were published at national and international conferences. A popular science paper was also published in the leading Hungarian journal (Élet és Tudomány/Life and Science). Furthermore, the manuscript of the second edition of the Advanced Process Engineering Control book was finalized, with the anticipated publication date of November 2023 at DeGruyter. The simulators and the data sets generated during this MSCA will inform and enhance dozens of publications in the coming years, in addition to the ones produced and published during the fellowship itself.
This MSCA has pushed the frontiers of crystallization engineering in numerous ways. A platform-independent, flexible, and quick crystallization process simulator was developed in C language, which will cut the simulation time of arbitrary crystallization systems. This will be shared with the scientific community upon request. The idea of sequential mechanistic modeling/optimization and data mining framework was introduced, developed, and validated for PC processes, which is a premier in process systems engineering. This can be applied to virtually any other chemical process modeled with physical models. It is a highly promising tool for early-stage process screening and performance assessment to cut the overall process development time of new processes and enhance existing technologies' operation. Ultimately, this results in better, cleaner, and safer technologies that contribute to keeping our living standards and improving those in need.
This MSCA allowed the Fellow to develop agility with various experimental methodologies and helped him promote good practices to industrial and academic stakeholders. The practical manifestation of this was the experimental study that showed, on a proof of concept level, that combined cooling and antisolvent crystallization can be employed to enhance the autocatalytic nature of the PC, leading to faster de-racemization and better yield.
The program also supported the integration of the Fellow into the Hungarian educational system, with teaching activities in process control and design from 2023 Fall. The Fellow advised the diploma work of two undergraduate students and hired two graduate students from the Fall semester of 2022.
Impacts anticipated from the MSCA are increased and improved:
• the publication activity, the innovative nature of the developed hybrid mechanistic and data-driven modeling, and the practical experimental results are beyond expectations,
• industrial stakeholders from multiple companies were contacted, and numerous research and development projects are in the pipeline for the post-MSCA times,
• a large public audience was reached, and the research topic of this MSCA program and related subjects were communicated in an easily understandable way.
A final overarching impact is the enhanced public and industrial perception of the usefullness of the model-based crystallization engineering.
This MSCA allowed the Fellow to develop agility with various experimental methodologies and helped him promote good practices to industrial and academic stakeholders. The practical manifestation of this was the experimental study that showed, on a proof of concept level, that combined cooling and antisolvent crystallization can be employed to enhance the autocatalytic nature of the PC, leading to faster de-racemization and better yield.
The program also supported the integration of the Fellow into the Hungarian educational system, with teaching activities in process control and design from 2023 Fall. The Fellow advised the diploma work of two undergraduate students and hired two graduate students from the Fall semester of 2022.
Impacts anticipated from the MSCA are increased and improved:
• the publication activity, the innovative nature of the developed hybrid mechanistic and data-driven modeling, and the practical experimental results are beyond expectations,
• industrial stakeholders from multiple companies were contacted, and numerous research and development projects are in the pipeline for the post-MSCA times,
• a large public audience was reached, and the research topic of this MSCA program and related subjects were communicated in an easily understandable way.
A final overarching impact is the enhanced public and industrial perception of the usefullness of the model-based crystallization engineering.