NMR/MRI studies of drug diffusion in polymer melts
Lead Research Organisation:
University of Cambridge
Department Name: Chemical Engineering and Biotechnology
Abstract
Solid drug dispersions (SDDs) are increasingly being selected as a formulation strategy aimed at overcoming the low oral bioavailability typically associated with poorly soluble compounds. SDDs can be prepared by a number of methods including hot melt extrusion HME. The key challenges in producing an amorphous extruded product that performs consistently are the need to ensure that no residual crystalline drug remains after extrusion and that the product has a high drug content-uniformity.
One of the key parameters in understanding the behviour of the final product is to be able to measure (and ultimately predict) a true value for the self-diffusion coefficient of the drug in the liquid phase at high temperatures (Dself). We have recently shown it is possible to measure drug self-diffusion at HME temperatures using multi-nuclear pulsed field gradient (PFG) nuclear magnetic resonance giving us new insights into the dynamics and mass transport behaviour of APIs during hot melt extrusion processes.
The Ph.D. programme will involve a detailed study of all aspects of hot melt extrusion and will include building a high temperature NMR compatible cell to study drug diffusion in polymer melts. In addition to studying the API, typically by the use of 19F NMR, we also seek to exploit the use of 2H NMR and 13C NMR to study the dynamics of the polymer system itself.
One of the key parameters in understanding the behviour of the final product is to be able to measure (and ultimately predict) a true value for the self-diffusion coefficient of the drug in the liquid phase at high temperatures (Dself). We have recently shown it is possible to measure drug self-diffusion at HME temperatures using multi-nuclear pulsed field gradient (PFG) nuclear magnetic resonance giving us new insights into the dynamics and mass transport behaviour of APIs during hot melt extrusion processes.
The Ph.D. programme will involve a detailed study of all aspects of hot melt extrusion and will include building a high temperature NMR compatible cell to study drug diffusion in polymer melts. In addition to studying the API, typically by the use of 19F NMR, we also seek to exploit the use of 2H NMR and 13C NMR to study the dynamics of the polymer system itself.
Organisations
People |
ORCID iD |
| Michael Mantle (Primary Supervisor) | |
| Elena Pisa (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/N509620/1 | 01/10/2016 | 30/09/2022 | |||
| 1792248 | Studentship | EP/N509620/1 | 01/10/2016 | 31/03/2020 | Elena Pisa |
| Description | My work has been focused on the development of several novel applications of nuclear magnetic resonance (NMR) at high temperature, as well as other complementary methods to improve the understanding of drug (paracetamol) behaviour in polymer (copovidone) melts. Pulsed-field gradient diffusion NMR and 1D NMR imaging techniques provide information on the mass transport at a microscopic and macroscopic scale respectively, at temperatures relevant to hot-melt extrusion. 2D correlation spectroscopy (COSY), heteronuclear correlation (HETCOR), multiple quantum coherence (MQC) and nuclear Overhauser effect spectroscopy (NOESY) NMR of paracetamol/copovidon can examine which nuclei are coupled through chemical bonds and thus elucidate intermolecular interactions that stabilise the formulations. Solid state NMR is used to probe the amorphous state of the API and the microscopic structure of the extruded product (phase separation and re-crystallisatiom). Other approaches employed to help characterize this system was differential scanning calorimetry (DSC) and traditional oscillatory rheometry. 1D NMR imaging shows that there is a significant depression in the melting point of paracetamol (from 170 °C to <120 °C) in the presence of copovidone, as is typical in miscible systems. This opens the door to processing of these systems at lower temperatures, saving in costs and ensuring no thermal degradation. There is also a positive correlation between paracetamol's diffusivity in molten copovidone with both temperature and drug loading. The API molecular self-diffusivity in systems of 20-30% drug loading is almost two orders of magnitude slower than pure molten paracetamol at 170 °C. This suggests that polymer behaviour and paracetamol/copovidone interactions restrict API mobility and the data generated can be used to increase the accuracy of computational models. Preliminary COSY NMR results suggest that these intermolecular interactions are mainly mediated by hydrogen bonds between paracetamol and the PVP monomer of copovidone. Solid state 13C NMR spectra of a DoE study involving temperature, screw speed and drug loading for paracetamol/copovidone showed that all extruded samples were intimately mixed amorphous solid dispersions with no evidence of phase separation, even the ones processed at 140 °C (well below the melting point). The quantitative information about spin-diffusion path length from solid state 1H NMR T1 and T1rho relaxation experiments shows that extruded products from the DoE all have API domain sizes smaller than the limit of detection (3.5 nm), further supporting the claim that processing temperature can be safely decreased while maintaining final product quality. Interestingly, DoE samples with 30% paracetamol loading exhibited faster molecular diffusion coefficients at 150-170 °C than those with 20% loading and this was attributed to greater polymer mobility through plasticization. |
| Exploitation Route | Data on diffusion coefficient of drug in polymer melts can be used in computational models to create more accurate simulations of the hot-melt extrusion process. This is important to be able to predict final product performance in a cost- and time-efficient manner. |
| Sectors | Pharmaceuticals and Medical Biotechnology |
| Description | EUROMAR Conference July 2018, Nantes France |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | I presented a poster at the European Magnetic Resonance Meeting in July 2018 in Nantes, France. My poster was on proton high-temperature NMR studies of pharmaceutical formulations. I held some interesting discussions with people from Bruker, AstraZeneca, and other academics from the Universities of Manchester and Paris. |
| Year(s) Of Engagement Activity | 2018 |
| Description | SMASH Conference |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | I presented a poster at the Small Molecule NMR Conference (SMASH) in September 2019 in Porto, Portugal. My poster was on proton high-temperature NMR studies of hot-melt extruded pharmaceutical formulations. I held some interesting discussions with people from industry and academia. |
| Year(s) Of Engagement Activity | 2019 |