## 6 Borate-Stabilized Nicotinamide Riboside
### Solubility and Degradation Kinetics of Nicotinamide Riboside Borate  
The possibility that NR borate provides, at last, a stable form of NR should motivate the study of its effect in preclinical and clinical studies. Since borate esters are dynamic, with borate dissociating from NR upon dilution, we expect that the effects of NR borate should closely parallel the effects of NR. The solubility and degradation kinetics of NR borate were examined in various physiological media, including 0.1 N hydrochloric acid (pH 1.5), sodium acetate buffer (pH 5.0), water (pH 7.0), and phosphate-buffered saline (pH 7.4), using HPLC analysis. Furthermore, stability studies were conducted to investigate how different pH levels and temperatures influenced the degradation kinetics of NR borate. The results revealed significant variations in the solubility and stability of NR borate within the tested biological solutions. The solubility of NR borate was found to be pH-dependent, increasing as the pH level rose [257]. Using the shake-flask method at room temperature, the solubility of NR borate was evaluated. The measurements showed that NR borate had solubilities of 1972.7 \(\pm\) 15.4 mg/mL, 1060.5 \(\pm\) 31.0 mg/mL, and 926.0 \(\pm\) 34.4 mg/mL at pH 1.5, 5.0, and 7.4, respectively. These findings indicate that NR borate demonstrated high solubility in all three solutions with varying pH levels, meeting the standards outlined in the U.S. Pharmacopoeia recommendations [257] (Figure 2). Figure 1: NR borate mass spectrum: \({}^{11}\)B (\(m/z\) 281); \({}^{10}\)B (\(m/z\) 280). B: boron; NR: nicotinamide riboside. Figure 2: pH stability for NR borate. To investigate the spontaneity of NR borate degradation in various pH solutions, the Gibbs free energy (\(\Delta G\)) was calculated. The \(\Delta G\) value obtained for NR borate was 2.43 kcal/mol [257]. When examining NR borate as a nutritional supplement, it is important to investigate the generation of NAM and the ribose-borate complex, which acts as a physiological reservoir of B, as degradation byproducts. It is understood that the existence of anionic borate can impede the conversion of NR into NAM and trigger the activation of SIRT. While there is limited scientific data on the slight degradation of NR in simulated gastric fluids, substantial degradation seems to occur in the intestine due to its elevated pH levels [233]. The stability of NR borate is significantly influenced by neutral conditions, exemplified by the pH 7.4 employed in this study. In the Arrhenius model of NR borate degradation, the rate of degradation is higher at pH 7.4 compared to pH 1.5 and pH 5.0, supporting the notion that the degradation of NR borate is influenced by the concentration of HO\({}^{-}\) ions in the solution. It is crucial to exercise caution when using an aqueous solution of NR borate, particularly at high pH values where an excess of HO\({}^{-}\) ions can accelerate the degradation process due to hydrolysis. Our findings suggest that there may be a slightly distinct mechanism of degradation for NR and NR borate under acidic conditions compared to neutral or alkaline conditions. Consequently, this model can serve as a general reference for comprehending the stability of NR borate in various buffered solutions. Additionally, temperature plays a role in the content of NR borate in solution, with a 10 \({}^{\circ}\)C increase approximately doubling its degradation rate under any pH condition. The estimation of _log_P is crucial for predicting the permeability of NR borate. It is well established that compounds with estimated _log_P values less than 1.72 exhibit low permeability. According to the Biopharmaceutical Classification System (BCS), NR borate is classified as Class III due to its high solubility but anticipated low permeability, as indicated by a _log_P value of \(-\)4.17. This physiological characteristic may be linked to the proportion of released degradation products.