| Autor: |
Coutinho AL; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States., Hom K; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States., Polli JE; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States. |
| Jazyk: |
angličtina |
| Zdroj: |
Molecular pharmaceutics [Mol Pharm] 2024 Nov 01. Date of Electronic Publication: 2024 Nov 01. |
| DOI: |
10.1021/acs.molpharmaceut.4c00359 |
| Abstrakt: |
Amorphous solid dispersions (ASDs) function in part via a "parachute effect", i.e., polymer-enabled prolonged drug supersaturation, presumably through drug-polymer interactions in the liquid state. We aim to expand the utility of liquid state nuclear magnetic resonance ( 1 HNMR) to streamline polymer selection for ASDs. Our hypothesis is that strong molecular interactions between polymer and drug in 1 HNMR anticipate reduced precipitation kinetics in supersaturation studies. For three drug-polymer pairs (i.e., etravirine with each HPMC, HPMCAS-M, and PVP-VA), 1 HNMR findings were compared to more common supersaturation studies. Drug-polymer interactions were assessed by saturation transfer difference NMR (STD-NMR) and T 1 relaxation time. 2D- 1 H NOESY experiments were also performed. Supersaturation studies involved precipitation inhibition using the solvent-shift methodology. The results from STD-NMR and T 1 relaxation time indicate etravirine bound preferably to HPMCAS-M > HPMC ≫ PVP-VA. STD-NMR and T 1 relaxation time yielded insight into which fragments of etravirine structure bind with HPMCAS-M and HPMC. The strong interactions from STD-NMR and T 1 relaxation time changes indicated that HPMCAS-M and HPMC, but not PVP-VA, are suitable polymers to maintain etravirine supersaturation and inhibit drug precipitation. 2D- 1 H NOESY results corroborate the findings of STD-NMR and T 1 relaxation time, showing that etravirine interacts preferably to HPMCAS-M than to PVP-VA. Supersaturation studies using solvent-shift technique corroborated our hypothesis as predissolved HPMCAS-M and HPMC, but to a less extent PVP-VA, markedly promoted etravirine supersaturation and inhibited drug precipitation. Supersaturation studies agreed with STD-NMR and T 1 relaxation time predictions, as HPMC and HPMCAS-M maintained etravirine in solution for longer time than PVP-VA. The results show promise of 1 HNMR to streamline polymer selection in a nondestructive and resource sparing fashion for subsequent ASD development. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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