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

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 1 H– 13 C through-space heteronuclear correlation experiments identify proximity between aromatic protons in acetaminophen with cellulose backbone protons in HPMC-AS. We also show that 14 N– 1 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.

Microbiological-Chemical Sourced Chondroitin Sulfates Protect Neuroblastoma SH-SY5Y Cells against Oxidative Stress and Are Suitable for Hydrogel-Based Controlled Release

“…This hypothesis was supported by the results from DMMB assay: CS-A,C is released faster than CS-A,C, K, L; and CS-A,C, K, L is delivered much faster from P.Ethanol.0 than P.NaOH.0. The investigation of drug–polymer interactions (e.g., by FTIR or NMR spectroscopy [ 71 ]) was out of the scope of this work, but our results confirmed a structural difference between the two CS polysaccharides and the influence of sulfation pattern also on diffusion.…”

Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs

“…IR and DSC are rapid methods to identify such solids. A complete understanding of the thermodynamics driving the components to achieve the amorphous state without transformation to the low-energy crystalline form is a topic of recent studies in pharmaceutical systems. − Coamorphous solids are a relatively recent entry to pharmaceutical formulation in contrast to salts, cocrystals, and eutectics. Broadly, two categories of techniques are reported to prepare coamorphous solids: the amorphous drug is formed as a melt followed by rapid cooling (quenching) or fast removal of solvent by rapid precipitation of the drug from solution.…”

Optimisation of 1H PMLG homonuclear decoupling at 60 kHz MAS to enable 15N–1H through-bond heteronuclear correlation solid-state NMR spectroscopy

“…[9][10][11][12][13][14] In particular, 1 H detection is advantageous for the identification of specific correlations to nuclei with low gyromagnetic ratio, , such as the two naturalabundant isotopes of nitrogen, 14 N and 15 N. Our focus here is on the spin I = 1/2 15 N, though it is to be noted that there is increasing application of 14 N-1 H experiments for the much higher natural abundance (99.6%) spin I = 1 nucleus. [15][16][17][18][19][20][21][22] The low sensitivity of 15 N, associated with its low natural abundance and gyromagnetic ratio, can be overcome by the use of 15 N-1 H correlation experiments with proton acquisition, thanks to the high natural abundance and  that characterise protons, provided that fast MAS can achieve sufficient 1 H line narrowing. [23][24][25][26] We note that an 15 N-detected MAS-J-HMQC 1 H- 15 N two-dimensional spectrum has also been recorded at natural abundance and 12.5 kHz MAS using Frequency Switched Lee-Goldburg (FSLG) 1 H homonuclear decoupling.…”

“…14 N-1 H experiments for the much higher natural abundance (99.6%) spin I = 1 nucleus. [15][16][17][18][19][20][21][22] The low sensitivity of 15 N, associated with its low natural abundance and gyromagnetic ratio, can be overcome by the use of 15 N-1 H correlation experiments with proton acquisition, thanks to the high natural abundance and g that characterise protons, provided that fast MAS can achieve sufficient 1 H line narrowing. [23][24][25][26] We note that an 15 N-detected MAS-J-HMQC 1 H-15 N two-dimensional spectrum has also been recorded at natural abundance and 12.5 kHz MAS using Frequency Switched Lee-Goldburg (FSLG) 1 H homonuclear decoupling.…”