Periodic Reporting for period 4 - STRUCTURE (De novo structural elucidation of functional organic powders at natural isotopic abundance)
Okres sprawozdawczy: 2022-07-01 do 2023-12-31
In the permanent quest for new materials adapted for specific applications, materials scientists need to establish relationships between the structure and the properties of the material in its end-use solid form. In other words, they need to access the structure of materials to the atomic scale. Unfortunately, in their final form, functional materials often exist as very small particles, for which no general and reliable structure-determination technique exists. Moreover, these materials are often employed in their crystalline form. However, controlling the outcome of crystallization is still out of reach because the mechanisms underlying the formation of a crystal remain essentially unknown. This scientific gap has major consequences for polymorphic materials (i.e. that can crystallize in different forms), as each polymorph has different properties. With no knowledge of the crystallization mechanisms, the outcome of crystallization cannot be controlled, which in turn prevents to control the material’s properties.
Overall, the lack of a general and reliable method for atomic-level structural analysis of polymorphic molecular solids not only prevents accurate characterization of the final powder structure, but also limits the ability to observe the structural changes occurring during the formation of the end-use solid form, hence hampering the ability to control how a specific polymorph is produced.
The aim of STRUCTURE is to develop innovative experimental methods for structure determination of molecular solids based on sensitivity-enhanced solid-state nuclear magnetic resonance (NMR), to:
a) access the atomic-level structure of solid, sub-um sized particles or agglomerates that are currently difficult or impossible to characterize using standard techniques;
b) investigate crystallizing solutions with time at an atomic level and decipher the structural process leading to the formation of a specific polymorph.
STRUCTURE introduced new experimental NMR methods to tackle structure determination in challenging solid samples, whose structure might evolve with time. Results were obtained on the characterization of the structure and the morphology of powdered polymorphic molecular solids relevant for pharmaceutics. STRUCTURE also introduced hyperpolarized-NMR methods to study the temporal evolution of a crystallizing solution at the atomic scale. These methods enabled the stabilization, detection and characterization of transient species forming during crystallization from solution, both in the bulk and under confinement.
The results obtained by STRUCTURE mark a significant stride towards bridging a longstanding scientific gap by offering new experimental tools to look into the mechanistic aspects of the formation and transformation of a solid at the atomic scale — an area of ongoing debate in the scientific literature. Looking ahead, the application of these methods might open new pathways towards mastering the control of material properties through deliberate manipulation of the crystallization process. The implications of these discoveries extend beyond this project, opening up new horizons in materials science and setting the stage for advancements that could redefine the landscape of solid material control and design.
Overall, the lack of a general and reliable method for atomic-level structural analysis of polymorphic molecular solids not only prevents accurate characterization of the final powder structure, but also limits the ability to observe the structural changes occurring during the formation of the end-use solid form, hence hampering the ability to control how a specific polymorph is produced.
The aim of STRUCTURE is to develop innovative experimental methods for structure determination of molecular solids based on sensitivity-enhanced solid-state nuclear magnetic resonance (NMR), to:
a) access the atomic-level structure of solid, sub-um sized particles or agglomerates that are currently difficult or impossible to characterize using standard techniques;
b) investigate crystallizing solutions with time at an atomic level and decipher the structural process leading to the formation of a specific polymorph.
STRUCTURE introduced new experimental NMR methods to tackle structure determination in challenging solid samples, whose structure might evolve with time. Results were obtained on the characterization of the structure and the morphology of powdered polymorphic molecular solids relevant for pharmaceutics. STRUCTURE also introduced hyperpolarized-NMR methods to study the temporal evolution of a crystallizing solution at the atomic scale. These methods enabled the stabilization, detection and characterization of transient species forming during crystallization from solution, both in the bulk and under confinement.
The results obtained by STRUCTURE mark a significant stride towards bridging a longstanding scientific gap by offering new experimental tools to look into the mechanistic aspects of the formation and transformation of a solid at the atomic scale — an area of ongoing debate in the scientific literature. Looking ahead, the application of these methods might open new pathways towards mastering the control of material properties through deliberate manipulation of the crystallization process. The implications of these discoveries extend beyond this project, opening up new horizons in materials science and setting the stage for advancements that could redefine the landscape of solid material control and design.
The obtained results concerned:
- - The development of new NMR crystallography methods to access the molecular conformation of organic powders - By combining simulation work and NMR experiments, STRUCTURE provided new experimental tools for local structural analysis of organic solids, giving access to their molecular conformation.
- The development of new methods for atomic-level investigation of crystallizing solutions - Two distinct experimental approaches based on solid-state NMR were devised, which produced an increase in both the temporal and spatial resolution of the analysis of crystallizing systems. The team developed: an in-situ NMR approach, enabling the analysis of metastable polymorphs and their structural evolution; an ex-situ NMR DNP approach, enabling the atomic-level analysis of the different forms (solvated, amorphous, crystalline) coexisting into the crystallization medium at different time points. Importantly, this last development enabled the detection of pre-nucleation clusters present in the crystallization medium, which is a major advance. The ex-situ methods for crystallization analysis were also adapted to the investigation of crystallization processes occurring under confinement. The team developed a specific approach which relies on the use of hyperpolarizing porous matrices that have the double role of increasing the sensitivity of NMR and at the same time provide a confined environment for crystallization.
- The investigation of solid-solid transformations occurring between different polymorphs of the same molecular compound - The team developed an approach based on hyperpolarized NMR that could detect the presence of a minor polymorph (a few %) within a major polymorph and determine the distribution of the two solid phases within the solid particle without the need of isotopic enrichment and with no a priori morphological assumptions or complementary structural information.
Overall, the results of the project significantly contributed to expand the possibilities offered by NMR crystallography for the study of polymorphic organic solids by introducing novel NMR methods and practical ways of exploiting the power of hyperpolarized NMR for getting structural details on the formation of a crystal from solution, a subject which remains strongly debated in the scientific literature.
These results have been published in peer reviewed publications (>15), including 2 book chapters and 1 invited review article, and presented in international conferences (>25 invited talks). The results helped strengthen or create fruitful collaborations. The developed approaches were also presented to the general public through outreach activities and were recognized by several prizes.
- - The development of new NMR crystallography methods to access the molecular conformation of organic powders - By combining simulation work and NMR experiments, STRUCTURE provided new experimental tools for local structural analysis of organic solids, giving access to their molecular conformation.
- The development of new methods for atomic-level investigation of crystallizing solutions - Two distinct experimental approaches based on solid-state NMR were devised, which produced an increase in both the temporal and spatial resolution of the analysis of crystallizing systems. The team developed: an in-situ NMR approach, enabling the analysis of metastable polymorphs and their structural evolution; an ex-situ NMR DNP approach, enabling the atomic-level analysis of the different forms (solvated, amorphous, crystalline) coexisting into the crystallization medium at different time points. Importantly, this last development enabled the detection of pre-nucleation clusters present in the crystallization medium, which is a major advance. The ex-situ methods for crystallization analysis were also adapted to the investigation of crystallization processes occurring under confinement. The team developed a specific approach which relies on the use of hyperpolarizing porous matrices that have the double role of increasing the sensitivity of NMR and at the same time provide a confined environment for crystallization.
- The investigation of solid-solid transformations occurring between different polymorphs of the same molecular compound - The team developed an approach based on hyperpolarized NMR that could detect the presence of a minor polymorph (a few %) within a major polymorph and determine the distribution of the two solid phases within the solid particle without the need of isotopic enrichment and with no a priori morphological assumptions or complementary structural information.
Overall, the results of the project significantly contributed to expand the possibilities offered by NMR crystallography for the study of polymorphic organic solids by introducing novel NMR methods and practical ways of exploiting the power of hyperpolarized NMR for getting structural details on the formation of a crystal from solution, a subject which remains strongly debated in the scientific literature.
These results have been published in peer reviewed publications (>15), including 2 book chapters and 1 invited review article, and presented in international conferences (>25 invited talks). The results helped strengthen or create fruitful collaborations. The developed approaches were also presented to the general public through outreach activities and were recognized by several prizes.
- Development of a novel solid-state NMR approach that gives access to torsional angles in molecular fragments of organic molecular crystals containing carbon atoms. It constitutes a unique practical tool for determining the local geometry of molecular solids, particularly relevant for structure determination of polymorphic solids. The developed technology will be made applicable to the characterization of organic powders at natural isotopic abundance.
- Development and application of new experimental protocols that allow hyperpolarized NMR to be used for time-resolved, atomic-level investigation of crystallization from a solution, both in the bulk and under confinement. The developed approaches will be employed with the aim of trying to catch the first instants of phase formation/transformation and possibly shed light on the atomic-level mechanism of nucleation.
- Development of a hyperpolarized NMR method to study the morphology of solid particles constituted by a mixture of different polymorphs of a given organic compound. This approach does not require any a priori structural assumption, and it can be applied even when the polymorphs have similar spectroscopic response in terms of their chemical shifts. This method might help identify the early onset of polymorphic transformation of active pharmaceutical ingredients in drug tablets.
- Development and application of new experimental protocols that allow hyperpolarized NMR to be used for time-resolved, atomic-level investigation of crystallization from a solution, both in the bulk and under confinement. The developed approaches will be employed with the aim of trying to catch the first instants of phase formation/transformation and possibly shed light on the atomic-level mechanism of nucleation.
- Development of a hyperpolarized NMR method to study the morphology of solid particles constituted by a mixture of different polymorphs of a given organic compound. This approach does not require any a priori structural assumption, and it can be applied even when the polymorphs have similar spectroscopic response in terms of their chemical shifts. This method might help identify the early onset of polymorphic transformation of active pharmaceutical ingredients in drug tablets.