Drug-Polymer Interactions in Acetaminophen/ Hydroxypropylmethylcellulose Acetyl Succinate Amorphous Solid Dispersions Revealed by Multidimensional Multinuclear Solid-State NMR Spectroscopy



Pugliese, Andrea, Toresco, Michael, McNamara, Daniel, Iuga, Dinu, Abraham, Anuji, Tobyn, Michael, Hawarden, Lucy E and Blanc, Frederic ORCID: 0000-0001-9171-1454
(2021) Drug-Polymer Interactions in Acetaminophen/ Hydroxypropylmethylcellulose Acetyl Succinate Amorphous Solid Dispersions Revealed by Multidimensional Multinuclear Solid-State NMR Spectroscopy. MOLECULAR PHARMACEUTICS, 18 (9). pp. 3519-3531.

Access the full-text of this item by clicking on the Open Access link.
[thumbnail of MS ID mp-2021-00427e.R1 - reviewed manuscript.pdf] Text
MS ID mp-2021-00427e.R1 - reviewed manuscript.pdf - Author Accepted Manuscript

Download (1MB) | Preview

Abstract

The bioavailability of insoluble crystalline active pharmaceutical ingredients (APIs) can be enhanced by formulation as amorphous solid dispersions (ASDs). One of the key factors of ASD stabilization is the formation of drug-polymer interactions at the molecular level. Here, we used a range of multidimensional and multinuclear nuclear magnetic resonance (NMR) experiments to identify these interactions in amorphous acetaminophen (paracetamol)/hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) ASDs at various drug loadings. At low drug loading (<20 wt %), we showed that <sup>1</sup>H-<sup>13</sup>C through-space heteronuclear correlation experiments identify proximity between aromatic protons in acetaminophen with cellulose backbone protons in HPMC-AS. We also show that <sup>14</sup>N-<sup>1</sup>H heteronuclear multiple quantum coherence (HMQC) experiments are a powerful approach in probing spatial interactions in amorphous materials and establish the presence of hydrogen bonds (H-bond) between the amide nitrogen of acetaminophen with the cellulose ring methyl protons in these ASDs. In contrast, at higher drug loading (40 wt %), no acetaminophen/HPMC-AS spatial proximity was identified and domains of recrystallization of amorphous acetaminophen into its crystalline form I, the most thermodynamically stable polymorph, and form II are identified. These results provide atomic scale understanding of the interactions in the acetaminophen/HPMC-AS ASD occurring via H-bond interactions.

Item Type: Article
Uncontrolled Keywords: acetaminophen (paracetamol), hydroxypropylmethylcellulose acetyl succinate (HPMC-AS), amorphous solid dispersion, solid-state NMR, drug-polymer interactions, multidimensional NMR
Divisions: Faculty of Science and Engineering > School of Physical Sciences
Depositing User: Symplectic Admin
Date Deposited: 13 Aug 2021 07:23
Last Modified: 18 Jan 2023 21:33
DOI: 10.1021/acs.molpharmaceut.1c00427
Open Access URL: https://pubs.acs.org/doi/10.1021/acs.molpharmaceut...
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3133272