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David C. Paik, Xia Li, Yongjun Li, Stephen L. Trokel, Nicholas J. Turro; Aliphatic β-nitroalcohols For Therapeutic Corneoscleral Cross-linking: Chemical Stability Studies Using 1H-NMR. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1514.
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The ability to selectively enhance the biomechanical properties of a given tissue in vivo could have widespread clinical utility. Our recent studies suggest that aliphatic β-nitro alcohols (BNAs) may represent a useful class of compounds for use as in vivo therapeutic corneoscleral cross-linking agents. In addition, higher order nitroalcohols (HONAs), which include a nitrodiol and nitrotriol, exhibit much greater tissue cross-linking efficacy than their nitromonol counterparts. Thus, the current study was undertaken in order to determine the chemical stability of these compounds under long-term storage conditions.
Two mono-nitroalcohols (2-nitroethanol=2ne and 2-nitro-1-propanol=2nprop) and two HONAs, a nitrodiol (2-methyl-2-nitro-1,3-propanediol=MNPD), and a nitrotriol (2-hydroxymethyl-2-nitro-1,3-propanediol=HNPD) were monitored for chemical stability by 1H-NMR for up to 7 months. Each compound was studied at two concentrations (1% and 10%) either in unbuffered H2O or 0.2 M NaH2PO4/Na2HPO4 (pH=5), for a total of 4 conditions for each compound. The 1H-NMR spectra for the starting material was compared to subsequent spectra. The formation of new peaks over time indicated decomposition of the starting material and hence chemical instability.
Typical 1H-NMR spectra were identified for each of the compounds tested and were in agreement with existing literature. Unbuffered solutions maintained a pH in the range of 7.0- 7.14. Under all 4 of the conditions studied, both the nitrodiol (MNPD) and nitrotriol (HNPD) were stable for the duration of 7 months showing no change in the 1H-NMR spectrum. 2nprop was stable under all conditions at 10 days but became unstable under all conditions at 3 months. 2ne was the most unstable of all the compounds tested, becoming unstable in unbuffered solution at 10 days. No effort was made to identify decomposition products as this was not the intent of the study.
HONAs exhibit excellent chemical stability under long-term storage conditions. In contrast, the nitromonols tested are significantly less stable. Because compound stability is important from a pharmaceutical standpoint, these findings are relevant to translation of this technology into clinical use.
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