Periodic Reporting for period 2 - CryForm (Crystal Engineering the New Generation of Sustainable, Biocompatible and Stimuli Responsive Formulations for the Delivery of Active Ingredients)
Reporting period: 2023-04-01 to 2024-09-30
This ERC starting grant 2020 “Crystal Engineering the New Generation of Sustainable, Biocompatible and Stimuli Responsive Formulations for the Delivery of Active Ingredients” (CryForm) project will develop innovative natural crystals for the design of new formulations easily soluble and able to deliver active ingredients in a controlled way, to be used in the agrochemical, pharmaceutical and food industry.
Description of the research project
Recent progress in pharmacology and biotechnology has led to a dramatic increase in power and specificity of new generation drugs, active agrochemical ingredients and food nutraceuticals. At the same time, a problem remains in making these substances water soluble, because of their high molecular weight and complex structure. Multiphase systems (such as emulsions, foams and creams) can solve this problem but are traditionally produced with synthetic stabilizing agents, which can make them unsafe and contribute to CO2 production.
Cryform aims at replacing synthetic stabilizing agents with crystalline materials that are natural, biocompatible and biodegradable, that can enable the design of innovative multiphase formulations.
The project has three fundamental objectives that will make this “revolution” possible: the study of the relation between crystalline structure and macroscopic properties of solid particles, the analysis of the thermodynamic and kinetic mechanisms of crystal nucleation and growth, as well as and the understanding of the role of large biomolecules in in the kinetic stability of solid crystals.
These elements will allow substantial progress of the current fundamental understanding of crystallization of organic materials and allow the development of formulations that can be used for pharmaceutical, agrochemical and food products that are safer, more sustainable and also more affordable.
Impact on society
The project tackles a major crystal engineering challenge and will generate new knowledge essential for the whole crystallization community. In particular, it will enable the design of biocompatible, safe and sustainable crystals to be used for pharmaceutical and cosmetic formulations, and to develop new products for the food and agriculture industry that are able of controlled release of active ingredients.
In general, the project will contribute to the development of more sustainable manufacturing processes also at the industrial scale and will help the transition of the European Union to a modern and competitive economy, efficiently using resources, as it is necessary to achieve the European Green Deal.
Description of the research project
Recent progress in pharmacology and biotechnology has led to a dramatic increase in power and specificity of new generation drugs, active agrochemical ingredients and food nutraceuticals. At the same time, a problem remains in making these substances water soluble, because of their high molecular weight and complex structure. Multiphase systems (such as emulsions, foams and creams) can solve this problem but are traditionally produced with synthetic stabilizing agents, which can make them unsafe and contribute to CO2 production.
Cryform aims at replacing synthetic stabilizing agents with crystalline materials that are natural, biocompatible and biodegradable, that can enable the design of innovative multiphase formulations.
The project has three fundamental objectives that will make this “revolution” possible: the study of the relation between crystalline structure and macroscopic properties of solid particles, the analysis of the thermodynamic and kinetic mechanisms of crystal nucleation and growth, as well as and the understanding of the role of large biomolecules in in the kinetic stability of solid crystals.
These elements will allow substantial progress of the current fundamental understanding of crystallization of organic materials and allow the development of formulations that can be used for pharmaceutical, agrochemical and food products that are safer, more sustainable and also more affordable.
Impact on society
The project tackles a major crystal engineering challenge and will generate new knowledge essential for the whole crystallization community. In particular, it will enable the design of biocompatible, safe and sustainable crystals to be used for pharmaceutical and cosmetic formulations, and to develop new products for the food and agriculture industry that are able of controlled release of active ingredients.
In general, the project will contribute to the development of more sustainable manufacturing processes also at the industrial scale and will help the transition of the European Union to a modern and competitive economy, efficiently using resources, as it is necessary to achieve the European Green Deal.
At the time of the mid-report period, albeit with some delays, all WPs have started. Due to the unavailability of the laboratory space and the delays in receiving some equipment in the first reporting period (18 months) we focused on the modelling work, we took advantage of existing and newly formed collaboration with other research institutions (University of Leeds, Imperial College London, Università di Torino, CNR di Bari) and industrial partners (Nestlé) to access specific laboratory equipment and, finally we performed experiments at large research facilities via a peer-reviewed application process (European, British and Italian synchrotron, ESRF, Diamond and Elettra).
As part of a collaboration with the University of Leeds we explored the crystallization behaviour of natural sugars and collected crystallographic and physical data (e.g. solubility, thermal behaviour). With the University of Leeds and Imperial College London we studied the relationship between crystal structure of a natural flavonoid molecule and its surface properties, using molecular modelling and inverse gas chromatography available at Imperial College. Both studies were published on two different papers in the ACS journal Crystal Growth and Design and are part of the tasks envisaged for WP1.
In collaboration with the university of Leeds and the British synchrotron (Diamond Light source), we studied the stabilization mechanisms of cocoa butter crystals based oleofoams that can be used as topical delivery media or for food formulations. The work was published on the ACS journal Langmuir and is part of the project’s WP1 and WP4. In collaboration with the university of Leeds, we kept working on cocoa butter oleogels (the precursors of oleofoams) and published a review of Food Hydrocolloids and an original pape on Advance Materials interfaces on the use of cocoa butter oleogels to produce emulsions. We have another paper just accepted on Food Hydrocolloids on the use of cocoa butter oleogels as double emulsion stabilizers.
Since the end of the laboratory refurbishment (July 2022) we started actively working on WP1, focussing on solid form screening with the purchase Crystal16 and CrystalBreeder (equipment specified in the costing plan), particle characterization with chemical force microscopy and formulation characterization with Raman confocal microscopy. We published a paper on Crystal Growth and Design related to the solid form landscape of quercetin, a natural polyphenol, which was determind as part of a collaboration with CNR Bari and università di Torino.
At the mid-report time two postdoctoral researchers and four PhD students are working on the project; with the plan of hiring a further PhD student (part-time on the grant, looking at colloidal formulations and their performance). One of the PhD scholarship has been co-funded by the Cambridge Crystallographic Data Centre, which agreed to the ERC terms and conditions.
We were awarded several days of beamtime at ESRF, Diamond Light Source and Elettra, and started internal collaborations at Politecnico di Torino and with the University of Bologna, resulting in two publications on Chemistry Communication and the European Journal of Pharmaceutical Sciences. In collaboration with three different syncrothrons (ESRF, Elettra and Diamond Light Source) we worked on understanding how tryglyceride composition affect the type, number and stability of polymorphs forming in edible fat mixtures.
As part of a collaboration with the University of Leeds we explored the crystallization behaviour of natural sugars and collected crystallographic and physical data (e.g. solubility, thermal behaviour). With the University of Leeds and Imperial College London we studied the relationship between crystal structure of a natural flavonoid molecule and its surface properties, using molecular modelling and inverse gas chromatography available at Imperial College. Both studies were published on two different papers in the ACS journal Crystal Growth and Design and are part of the tasks envisaged for WP1.
In collaboration with the university of Leeds and the British synchrotron (Diamond Light source), we studied the stabilization mechanisms of cocoa butter crystals based oleofoams that can be used as topical delivery media or for food formulations. The work was published on the ACS journal Langmuir and is part of the project’s WP1 and WP4. In collaboration with the university of Leeds, we kept working on cocoa butter oleogels (the precursors of oleofoams) and published a review of Food Hydrocolloids and an original pape on Advance Materials interfaces on the use of cocoa butter oleogels to produce emulsions. We have another paper just accepted on Food Hydrocolloids on the use of cocoa butter oleogels as double emulsion stabilizers.
Since the end of the laboratory refurbishment (July 2022) we started actively working on WP1, focussing on solid form screening with the purchase Crystal16 and CrystalBreeder (equipment specified in the costing plan), particle characterization with chemical force microscopy and formulation characterization with Raman confocal microscopy. We published a paper on Crystal Growth and Design related to the solid form landscape of quercetin, a natural polyphenol, which was determind as part of a collaboration with CNR Bari and università di Torino.
At the mid-report time two postdoctoral researchers and four PhD students are working on the project; with the plan of hiring a further PhD student (part-time on the grant, looking at colloidal formulations and their performance). One of the PhD scholarship has been co-funded by the Cambridge Crystallographic Data Centre, which agreed to the ERC terms and conditions.
We were awarded several days of beamtime at ESRF, Diamond Light Source and Elettra, and started internal collaborations at Politecnico di Torino and with the University of Bologna, resulting in two publications on Chemistry Communication and the European Journal of Pharmaceutical Sciences. In collaboration with three different syncrothrons (ESRF, Elettra and Diamond Light Source) we worked on understanding how tryglyceride composition affect the type, number and stability of polymorphs forming in edible fat mixtures.
Some of the major scientific achievements at the time of the mid-report are:
- the development of a strategy to use co-crystals to manipulate surface properties of a compound (hydrophilicity/hydrophobicity and rugosity);
- better understanding, based on synthonic modelling and experiments (contact angle, atomic force microscopy, scanning electron microscopy, on how crystal structure affects surface properties and stability for curcumin and quercetin different solid phases
- understanding of the effect of crystal size and shape distribution on the stability of multiphase systems
- development of single and double emulsions with cocoa butter oleogels
- development of novel multiphase soft materials using agri-food residues (e.g. rice bran wax)
- understanding of the tryglycerides composition on the crystallization behaviour of natural edible fats
We have two manuscripts under review related to these topics and three further manuscripts in preparation.
We plan to conclude WP1 within this year, which is slightly later than expected but we started the work on co-crystals that was not originally planned. We hope to develop modelling and experimental tools to produce solid forms (e.g. co-crystals, solvates, hydrates) with tailored surface properties for Pickering stabilization.
WP2 has been delayed several months, due to the late delivery of the Raman microscope but we are now hoping to understand the effect of surface properties on the behaviour of crystals at interfaces using Raman confocal microscopy and X-ray tomography.
WP3 and WP4 have started but we hope to complete them in time to enable the design of complex multiphase systems with tailored kinetic of release. We will do this experimentally but also using modelling. This last task was not initially planned in the project but is the result of a collaboration with colleagues from Politecnico di Torino.
- the development of a strategy to use co-crystals to manipulate surface properties of a compound (hydrophilicity/hydrophobicity and rugosity);
- better understanding, based on synthonic modelling and experiments (contact angle, atomic force microscopy, scanning electron microscopy, on how crystal structure affects surface properties and stability for curcumin and quercetin different solid phases
- understanding of the effect of crystal size and shape distribution on the stability of multiphase systems
- development of single and double emulsions with cocoa butter oleogels
- development of novel multiphase soft materials using agri-food residues (e.g. rice bran wax)
- understanding of the tryglycerides composition on the crystallization behaviour of natural edible fats
We have two manuscripts under review related to these topics and three further manuscripts in preparation.
We plan to conclude WP1 within this year, which is slightly later than expected but we started the work on co-crystals that was not originally planned. We hope to develop modelling and experimental tools to produce solid forms (e.g. co-crystals, solvates, hydrates) with tailored surface properties for Pickering stabilization.
WP2 has been delayed several months, due to the late delivery of the Raman microscope but we are now hoping to understand the effect of surface properties on the behaviour of crystals at interfaces using Raman confocal microscopy and X-ray tomography.
WP3 and WP4 have started but we hope to complete them in time to enable the design of complex multiphase systems with tailored kinetic of release. We will do this experimentally but also using modelling. This last task was not initially planned in the project but is the result of a collaboration with colleagues from Politecnico di Torino.