New project will examine the surface properties of drug polyAmorphs
The project “Unraveling the molecular mechanisms of surface and bulk mobility in structurally related amorphous drugs” has received funding from NNF as part of the Project Grants in the Natural and Technical Sciences 2023.
![Professor Thomas Rades and Assistant Professor Inês Catarina Batista Martins. Professor Thomas Rades and Assistant Professor Inês Catarina Batista Martins.](/images/news/2024/IMG_3210_red_1100_x_600.jpg)
Inês Catarina Batista Martins and Professor Thomas Rades will conduct the research – and Inês will take up a position as Assistant Professor as of 1st of June.
Based on discoveries made in an earlier project
The new NNF project is based on findings from an earlier DFF project where the team discovered the occurrence of polyamorphism in the drug hydrochlorothiazide. This study, together with the proposed NNF project, will be important for the potential design of amorphous forms of drugs with improved solubility and physical stability to be incorporated in pharmaceutical dosage forms.
In the DFF project, Thomas and Inês investigated the formation and the bulk physicochemical properties of different amorphous forms (polyamorphs) of hydrochlorothiazide as well as elucidated their molecular-level organization (‘structure’) using a combination of experimental and computational methods.
Normal drug molecules are usually used in pharmaceutical dosage forms as crystals. The long range order of these crystalline forms can vary and these solids are called polymorphs, meaning that they can have “many (crystalline) forms”. In contrast, an amorphous form is a material without long range order – amorphous means “no form”.
However, while the molecules in a crystalline material are highly ordered in specific ways, what the researchers here believe they have discovered is that the molecules in amorphous materials also may have various distinct forms (polyamorphs) and following this, various properties.
Polyamorphism is a solid-state phenomenon that has been highly debated in both materials and pharmaceutical communities, but has not been thoroughly investigated for organic molecules, such as drugs, until now.
Thomas Rades explains the research perspective of the new project: “What we want to find out is how common this polyamorphism is in pharmaceutically relevant materials. Scientists have largely not taken this into account. There is some diffuse knowledge that differently prepared amorphous forms behave differently, but that is where we are.”
Inês Catarina Batista Martins says that this new study will focus on the different polyamorphs from the DFF project:
“We are now aiming to understand what happens at the surface and in the bulk of these polyamorphs, because we know that molecular mobility is correlated with physical stability and the physical instability is one of the biggest issues of the amorphous forms.
For this, we will be investigating, not only the molecular mobility, but also how the molecules are interacting with each other at the surface and in the bulk of the different polyamorphs, using a combination of experimental and computational methods. This study should enable us to better understand the physical stability of amorphous forms.”
“From a more practical application point of view, if we can use the increased solubility properties of amorphous forms in our favor and at the same time stabilize the amorphous forms by using the information of how the molecules interact with each other, we will be able to ultimately design more stable and relevant polyamorphs. This may for example lead to a decrease in the amount of drug incorporated into a tablet or a higher bioavailability of the drug.” says Inês Martins.
How does the preparation of polyAmorphs influence bulk properties and surface properties? Visualisation of the DFF and NNF projects.
![How does the preparation of polyamorphs influence bulk properties and surface properties? Visualisation of the DFF and NNF projects.](/images/news/2024/Graphical_abstract_article_copy.jpg)
i) quench-cooling (QC)
ii) ball milling (BM)
and iii) spray drying (SD)
Each of these new polyamorphs have different molecular-level organizations (1.) and molecular mobility (2.). The molecules, ordered in a random way in the amorphous form, can take more or less time to organize themselves towards a crystalline form, as shown by the stop watches where the green polyamorph I is the fastest and the red polyamorph II is the slowest.
Different physical stabilities against crystallization are obtained for each polyamorph, as illustrated with the seesaws. All physicochemical properties (molecular mobility, structural relaxation time and physical stability) previously investigated are related to the bulk properties. The surface properties on the right side of the illustration are now the focus of the research activities in the new NNF project.
Inês and Thomas aim to take a step further into the emerging research area of polyamorphism and propose to investigate how molecular mobility (specifically at the surface of the material) affects the structure and stability of polyamorphs. The concept of molecular mobility at the surface can be visualized by the trucks (3.) with the different polyamorphs moving at different speeds on the road to crystallization.