Solid-state NMR analysis of crystalline and amorphous Indomethacin: An experimental protocol for full resonance assignments

Lu, Xingyu; Xu, Wei; Hanada, Masataka; Jermain, Scott V.; Williams, Robert O.; Su, Yongchao

doi:10.1016/j.jpba.2018.11.001

Cited by 35 publications

(50 citation statements)

References 25 publications

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“…The 1 H spectra of the ASDs (Figure b) show a cluster of signals around 5 and 1 ppm, corresponding to HPMC-AS, as well as additional resonances for the acetaminophen. As summarized in Table , in the 10 and 20 wt % ASDs, the aromatic proton signals (H d a and H e a ) are deshielded with respect to the crystalline counterpart, the small difference observed being typical of amorphization processes . Finally, the H g a and H h a signals merged into a single broad signal centered at 8.5 ppm, which correlates strongly with the 15 N signal as revealed by the 15 N CP HETCOR spectrum (Figure SI-5), potentially confirming the absence of deprotonation.…”

Section: Results and Discussionsupporting

confidence: 55%

“…In addition, 13 C NMR signals for C d I /C e I and quaternary carbons C f a show a small difference in chemical shifts of 2–3 ppm vs acetaminophen form I (Table ). This suggests a structural change in the amorphous systems ,, attributed to crystalline API conversion to its amorphous form and results from the absence of long-range 3D interactions (e.g., hydrogen bonding, π–π interactions) in the crystalline sample, resulting in variation of local electronic environments.…”

Section: Results and Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Results and Discussionsupporting

confidence: 55%

Section: Results and Discussionmentioning

confidence: 99%

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

et al. 2021

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“…1D 13 C and 15 N spectra of the physical mixture, ASD, and individual components are shown in Figure . For 13 C spectra, the signal at 169.1 ppm in the 13 C spectra is unambiguously assigned to the ketone site of KTZ, whereas 182.6 and 178.3 ppm are respectively assigned to the carboxyl sites of PAA and dimeric PAA based on previous studies . The formation of hydrogen bonds often shifts the peak toward the higher field because of the shielding effect.…”

Section: Resultsmentioning

confidence: 87%

“…For 13 C spectra, the signal at 169.1 ppm in the 13 C spectra is unambiguously assigned to the ketone site of KTZ, whereas 182.6 and 178.3 ppm are respectively assigned to the carboxyl sites of PAA and dimeric PAA based on previous studies. [14,31] The formation of hydrogen bonds often shifts the peak toward the higher field because of the shielding effect. Because there is no nitrogen atom in PAA molecule, all 15 N intensity comes from KTZ.…”

Section: C and 15 N Ssnmr Characterizations Of The Ex Situ Asdmentioning

confidence: 99%

In situ solid‐state NMR characterization of pharmaceutical materials: An example of drug‐polymer thermal mixing

Yin

Huang

Guan

et al. 2020

Magnetic Reson in Chemistry

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Pharmaceutical amorphous solid dispersions, a multicomponent system prepared by dispersing drug substances into polymeric matrix via thermal and mechanical processes, represent a major platform to deliver the poorly water-soluble drug. Microscopic properties of drug-polymer contacts play mechanistic roles in manipulating long-term physical stability as well as dissolution profiles. Although solid-state nuclear magnetic resonance has been utilized as an indispensable tool to probe structural details, previous studies are limited to ex situ characterizations. Our work provides likely the first documented example to investigate comelting of ketoconazole and polyacrylic acid, as a model system, in an in situ manner. Their physical mixture is melted and mixed in the solid-state nuclear magnetic resonance rotor under magic angle spinning at up to approximately 400 K. Critical structural events of molecular miscibility and interaction have been successfully identified. These results design and evaluate the instrumental and experimental protocols for real-time characterizations of the comelting of pharmaceutical materials.

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“…[27][28][29] Nevertheless, it should be noted that the spectral resolution of proton is not comparable to that of 13 C spectra, and proton-detected 13 C/ 1 H heteronuclear correlation (HETCOR) experiment is typically required for accurate proton resonance assignments and thus enabling rapid structural analysis. [30][31][32] Notably, in the conventional proton-detected HETCOR experiment (Figure 1a), 30,33 only around 1% of 1 H polarization is transferred to 13 C via the first cross polarization (CP) period for the natural abundance organic solids, while 99% of 1 H polarization is actually destroyed and wasted by the heteronuclear decoupling or HORROR (homonuclear rotary resonance) period 34 to fully eliminate the residual proton polarization before second CP transfer for proton detection.…”

mentioning

confidence: 99%

Rapid structural analysis of minute quantities of organic solids by exhausting 1H polarization in solid-state NMR spectroscopy at fast MAS

Yan

Zhang

2021

Preprint

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Solid-state nuclear magnetic resonance (NMR) is a powerful and indispensable tool for structural and dynamic studies of various challenging systems. Nevertheless, it often suffers from significant limitations due to the inherent low signal sensitivity when low- nuclei are involved. Herein, we report an efficient solid-state NMR approach for rapid and efficient structural analysis of minute amounts of organic solids. By encoding staggered chemical shift evolution in the indirect dimension and staggered acquisition in 1H dimension, a proton-detected homonuclear 1H/1H and heteronuclear 13C/1H chemical shift correlation (HETCOR) spectrum can be obtained simultaneously in a single experiment at fast magic-angle-spinning (MAS) conditions with barely increasing experimental time, compared to conventional proton-detected HETCOR experiment. We establish that abundant 1H polarization can be efficiently manipulated and fully utilized in proton-detected solid-state NMR spectroscopy for extraction of more critical structural information and thus reduction of total experimental time.

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Solid-state NMR analysis of crystalline and amorphous Indomethacin: An experimental protocol for full resonance assignments

Cited by 35 publications

References 25 publications

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

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

In situ solid‐state NMR characterization of pharmaceutical materials: An example of drug‐polymer thermal mixing

Rapid structural analysis of minute quantities of organic solids by exhausting 1H polarization in solid-state NMR spectroscopy at fast MAS

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