Using TD-NMR relaxometry to differentiate polymorphism of Active Pharmaceutical Ingredient – a study on anti-helminthic Mebendazole molecule

Time domain nuclear magnetic resonance (TD-NMR) plays an important role on material characterization, ensuring quality control on a different type of heterogeneous materials. The spin-lattice (T1) and spin-spin (T2) relaxation times depends on molecular dynamics for samples, in solid or liquid state. One recurrent problem on crystalized materials is the presence of different molecular arrangement, causing the formation of polymorphic materials. It is well acknowledged that different crystallin arrangements tend to present different physical-chemical properties, including stability and solubility. In Active Pharmaceutical Ingredients (API) different polymorphic conformations are intrinsically related with therapeutic efficiency. Therefore, the presence of API polymorphism is a matter of relevance for regulatory pharmaceutical agencies. So far, API polymorphism have been analyzed on TD-NMR in regards of percentage and crystalline structure (eg. solvates, salts, hydrates). Nevertheless, the use of T1 to characterize different polymorphs of the same molecule is sparse. Hence, the present work investigates the relaxometric profile of different polymorphic structures (inactive A and active C forms) of the anti-helminthic Mebendazole (MBZ). The MBZ samples were analyzed on a 0.49 T benchtop Bruker Minispec using inversion recovery pulse sequence. The T1 values were determined by multi exponential fitting and Inverse Laplace Transformation. The results show two T1 values for A form at 1.9 s and 8.4 s and relative area of 23 and 77%, respectively. The T1 values for C form were 1.0s and 6.2 s and relative areas of 23 and 77%, respectively. Therefore, the T1 values determined in benchtop TD-NMR spectrometer can be a low-cost technique for differentiating the polymorphic form A and C of MBZ. Consequently, T1 measured in TD-NMR spectrometers can be a alternative to the X rays diffractometry, that uses ionizing radiation or expensive high resolution solid state NMR spectroscopy.
Acknowledgments: FAPESP grant # 2021/12694-3