Enhanced Solid-State Nuclear Magnetic Resonance Spectroscopy of Amorphous Solid Dispersions for Pharmaceutical Sciences
Lead Research Organisation:
University of Liverpool
Department Name: Chemistry
Abstract
One of the greatest challenges faced in drug development is the low aqueous solubility of active pharmaceutical ingredients (APIs), inhibiting their biopharmaceutical performance.1 90% of molecules in drug discovery pipelines display poor water solubility which risks failure due to poor biological performance.2 Formation of amorphous solid dispersions (ASDs) can increase the bioavailability of poorly soluble drugs.3
ASDs consist of APIs in an amorphous state dispersed in an excipient matrix, showing high success in increasing the solubility of APIs.4 Polymers play a critical role in stabilising and inhibiting recrystallisation of the amorphous API in an ASD.5 Specific interactions between the API and polymer are known to aid miscibility in the dispersed systems. Polymer choice is imperative in ASD design to control the drug dissolution rate and stability, therefore an understanding of the interactions present within the dispersion are needed to inform their design.6 Hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) is the most widely used polymer in commercially available ASDs due to its ability to increase the solubility and dissolution of poorly soluble drugs whilst impeding drug recrystallisation.7
The ability to provide structural information of amorphous solids,8 identify drug recrystallisation mechanisms,9 and measure intermolecular interactions between different components of ASDs is why Nuclear Magnetic Resonance (NMR) spectroscopy is an ideal tool to investigate ASDs for increased solubility of APIs.10 General aims of this project include a focus on understanding how HPMC-AS stabilises amorphous APIs on a molecular level. Measurements will be made on ASDs containing HPMC-AS to identify spatial proximities, intermolecular interactions and site-specific interactions between the polymer and different amorphous drugs.11 From this, an understanding on the role HPMC-AS plays in ASDs can be obtained to inform the formulation of successful ASDs, increasing the number of medicines that can be brought to market and the number of diseases that can currently be treated.
(1) Schittny, A.; Huwyler, J.; Puchkov, M. Mechanisms of increased bioavailability through amorphous solid dispersions: a review. Drug Delivery 2020, 27 (1), 110-127.
(2) Kalepu, S.; Nekkanti, V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharmaceutica Sinica B 2015, 5 (5), 442-453.
(3) Butar-Butar, M. E. T.; Wathoni, N.; Ratih, H.; Wardhana, Y. W. Solid Dispersion Technology for Improving the Solubility of Antiviral Drugs. Pharmaceutical Sciences and Research 2023, 10 (1), 3.
(4) Iyer, R.; Petrovska Jovanovska, V.; Berginc, K.; Jaklic, M.; Fabiani, F.; Harlacher, C.; Huzjak, T.; Sanchez-Felix, M. V. Amorphous solid dispersions (asds): The influence of material properties, manufacturing processes and analytical technologies in drug product development. Pharmaceutics 2021, 13 (10), 1682.
(5) Liu, H.; Taylor, L. S.; Edgar, K. J. The role of polymers in oral bioavailability enhancement; a review. Polymer 2015, 77, 399-415.
(6) Hiew, T. N.; Zemlyanov, D. Y.; Taylor, L. S. Balancing solid-state stability and dissolution performance of lumefantrine amorphous solid dispersions: the role of polymer choice and drug-polymer interactions. Molecular pharmaceutics 2021, 19 (2), 392-413.
(7) Butreddy, A. Hydroxypropyl methylcellulose acetate succinate as an exceptional polymer for amorphous solid dispersion formulations: A review from bench to clinic. European Journal of Pharmaceutics and Biopharmaceutics 2022.
(8) Yuan, X.; Sperger, D.; Munson, E. J. Investigating miscibility and molecular mobility of nifedipine-PVP amorphous solid dispersions using solid-state NMR spectroscopy. Molecular pharmaceutics 2014, 11 (1), 329-337.
(9) Aso, Y.; Yoshioka, S.; Kojima, S. Relationship between the crystallization rates of amorphous nifedipine, phenobarbital, and flopropione, and their molecular mobility as measured by th
ASDs consist of APIs in an amorphous state dispersed in an excipient matrix, showing high success in increasing the solubility of APIs.4 Polymers play a critical role in stabilising and inhibiting recrystallisation of the amorphous API in an ASD.5 Specific interactions between the API and polymer are known to aid miscibility in the dispersed systems. Polymer choice is imperative in ASD design to control the drug dissolution rate and stability, therefore an understanding of the interactions present within the dispersion are needed to inform their design.6 Hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) is the most widely used polymer in commercially available ASDs due to its ability to increase the solubility and dissolution of poorly soluble drugs whilst impeding drug recrystallisation.7
The ability to provide structural information of amorphous solids,8 identify drug recrystallisation mechanisms,9 and measure intermolecular interactions between different components of ASDs is why Nuclear Magnetic Resonance (NMR) spectroscopy is an ideal tool to investigate ASDs for increased solubility of APIs.10 General aims of this project include a focus on understanding how HPMC-AS stabilises amorphous APIs on a molecular level. Measurements will be made on ASDs containing HPMC-AS to identify spatial proximities, intermolecular interactions and site-specific interactions between the polymer and different amorphous drugs.11 From this, an understanding on the role HPMC-AS plays in ASDs can be obtained to inform the formulation of successful ASDs, increasing the number of medicines that can be brought to market and the number of diseases that can currently be treated.
(1) Schittny, A.; Huwyler, J.; Puchkov, M. Mechanisms of increased bioavailability through amorphous solid dispersions: a review. Drug Delivery 2020, 27 (1), 110-127.
(2) Kalepu, S.; Nekkanti, V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharmaceutica Sinica B 2015, 5 (5), 442-453.
(3) Butar-Butar, M. E. T.; Wathoni, N.; Ratih, H.; Wardhana, Y. W. Solid Dispersion Technology for Improving the Solubility of Antiviral Drugs. Pharmaceutical Sciences and Research 2023, 10 (1), 3.
(4) Iyer, R.; Petrovska Jovanovska, V.; Berginc, K.; Jaklic, M.; Fabiani, F.; Harlacher, C.; Huzjak, T.; Sanchez-Felix, M. V. Amorphous solid dispersions (asds): The influence of material properties, manufacturing processes and analytical technologies in drug product development. Pharmaceutics 2021, 13 (10), 1682.
(5) Liu, H.; Taylor, L. S.; Edgar, K. J. The role of polymers in oral bioavailability enhancement; a review. Polymer 2015, 77, 399-415.
(6) Hiew, T. N.; Zemlyanov, D. Y.; Taylor, L. S. Balancing solid-state stability and dissolution performance of lumefantrine amorphous solid dispersions: the role of polymer choice and drug-polymer interactions. Molecular pharmaceutics 2021, 19 (2), 392-413.
(7) Butreddy, A. Hydroxypropyl methylcellulose acetate succinate as an exceptional polymer for amorphous solid dispersion formulations: A review from bench to clinic. European Journal of Pharmaceutics and Biopharmaceutics 2022.
(8) Yuan, X.; Sperger, D.; Munson, E. J. Investigating miscibility and molecular mobility of nifedipine-PVP amorphous solid dispersions using solid-state NMR spectroscopy. Molecular pharmaceutics 2014, 11 (1), 329-337.
(9) Aso, Y.; Yoshioka, S.; Kojima, S. Relationship between the crystallization rates of amorphous nifedipine, phenobarbital, and flopropione, and their molecular mobility as measured by th
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/T517975/1 | 01/10/2020 | 30/09/2025 | |||
| 2889117 | Studentship | EP/T517975/1 | 01/10/2023 | 31/07/2027 | Ronan Cosquer |