Understanding the physicochemical properties and degradation kinetics of nicotinamide riboside, a promising vitamin B3nutritional supplement

  • Michael T.D. Campbell
  • David S. Jones, Professor
  • Gavin P. Andrews
  • Shu Li
Keywords: Nicotinamide riboside, nutritional supplementation, physicochemical properties, degradation kinetics, in vitro testing


Nicotinamide riboside (NR), a newly recognised form of vitamin B3 and a precursor to nicotinamide adenine dinucleotide (NAD+), has been demonstrated to show therapeutic potential and the possibility of becoming a drug compound in addition to its proven role in rejuvenating ageing cells in mice. However, current literature is devoid of information relating to the physicochemical characterisation of NR and its respective impact upon formulation and final product processing. Here we report physicochemical properties of NR including pKa, log P, solubility, melting point, degradation mechanics, and kinetics, with a special focus on its stability under thermal and physiologically relevant conditions. A simple and rapid HPLC method confirms a base-catalysed hydrolysis degradation of NRCl to nicotinamide and sugar in simulated gastrointestinal (GI) fluids. Given the antagonising effect of nicotinamide against NR, the presented data have a profound impact on how NRCl should be handled both during formulation and storage to prevent formation and to limit accumulation of nicotinamide. The innovative combinatorial use of 1H NMR and Differential Scanning Calorimetry (DSC) was employed to investigate thermal events during NR melting. NRCl degrades upon melting and in solution undergoes hydrolysis in a buffer and in simulated intestinal environments. The results suggest that a proper and evidence-based formulation of NRCl is vital to enable further investigation and clinical analysis of this promising and novel nutrient. Any formulation would need to promote the stability of NRCl and protect it from hostile environments to prevent the accumulation of a potentially antagonistic degradation product. With the current work, we have filled a niche but vital gap in NR literature and the data presented may prove useful in furthering the understanding, specifically the formulation and processing of NRCl.


Download data is not yet available.


  1. Bieganowski P, Brenner C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell 2004; 117(4): 495–502. doi: 10.1016/s0092-8674(04)00416-7

  2. Trammell SA, Yu L, Redpath P, Migaud ME, Brenner C. Nicotinamide riboside is a major NAD+ precursor vitamin in cow milk. J Nutr 2016; 146(5): 957–63. doi: 10.3945/jn.116.230078

  3. Yang T, Chan NYK, Sauve AA. Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. J Med Chem 2007; 50(26): 6458–61. doi: 10.1021/jm701001c

  4. Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiol Aging 2013; 34(6):1581–8. doi: 10.1016/j.neurobiolaging.2012.12.005

  5. Cerutti R, Pirinen E, Lamperti C, Marchet S, Sauve AA, Li W, et al. NAD+-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease. Cell Metab 2014;19(6): 1042–9. doi: 10.1016/j.cmet.2014.04.001

  6. Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 2012;15(6): 838–47. doi: 10.1016/j.cmet.2012.04.022

  7. Lee HJ, Hong Y-S, Jun W, Yang SJ. Nicotinamide riboside ameliorates hepatic metaflammation by modulating NLRP3 inflammasome in a rodent model of type 2 diabetes. J Med Food 2015; 18(11): 1207–13. doi: 10.1089/jmf.2015.3439

  8. Brown KD, Maqsood S, Huang JY, Pan Y, Harkcom W, Li W, et al. Activation of SIRT3 by the NAD+ precursor nicotinamide riboside protects from noise-induced hearing loss. Cell Metab 2014; 20(6): 1059–68. doi: 10.1016/j.cmet.2014.11.003

  9. Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 2016; 352(6292): 1436–43. doi: 10.1126/science.aaf2693

  10. Trammell SAJ, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun 2016; 7: 12948. doi: 10.1038/ncomms12948

  11. Conze DB, Crespo-Barreto J, Kruger CL. Safety assessment of nicotinamide riboside, a form of Vitamin B3. Hum Exp Toxicol 2016; 35(11): 1149–60. doi: 10.1177/0960327115626254

  12. Lipinski CA, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997; 46(1–3): 3–26. doi: 10.1016/S0169-409X(00)00129-0

  13. Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995;12: 413–20. doi: 10.1023/A:1016212804288

  14. Malz F, Jancke H. Validation of quantitative NMR. J Pharm Biomed Anal 2005; 38(5): 813–23. doi: 10.1016/j.jpba.2005.01.043

  15. Dressman JB, Krämer J. Pharmaceutical dissolution testing. Boca Raton, FL: Taylor & Francis; 2005, 429 p.

  16. Stegemann S, Leveiller F, Franchi D, de Jong H, Lindén H. When poor solubility becomes an issue: from early stage to proof of concept. Eur J Pharm Sci 2007; 31(5): 249-61. doi: 10.1016/j.ejps.2007.05.110

  17. Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast Sir2 and human SIRT1. J Biol Chem 2002; 277(47): 45099–107. doi: 10.1074/jbc.M205670200

  18. Jackson MD, Schmidt MT, Oppenheimer NJ, Denu JM. Mechanism of nicotinamide inhibition and transglycosidation by Sir2 histone/protein deacetylases. J Biol Chem 2003; 278(51): 50985–98. doi: 10.1074/jbc.M306552200

  19. Sauve AA, Schramm VL. Sir2 regulation by nicotinamide results from switching between base exchange and deacetylation chemistry. Biochemistry 2003; 42(31): 9249–56. doi: 10.1021/bi034959l

  20. Klein S, Dressman JB, Butler J, Hempenstall JM, Reppas C. Media to simulate the postprandial stomach I. Matching the physicochemical characteristics of standard breakfasts. J Pharm Pharmacol 2004; 56(5): 605–10. doi: 10.1211/0022357023367

  21. Jantratid E, Janssen N, Chokshi H, Tang K, Dressman JB. Designing biorelevant dissolution tests for lipid formulations: case example –lipid suspension of RZ-50. Eur J Pharm Biopharm 2008; 69(2): 776–85. doi: 10.1016/j.ejpb.2007.12.010

  22. Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernäs H, Hussain AS, et al. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol Pharm 2004; 1(1): 85–96. doi: 10.1021/mp034006h

  23. Analytical Methods Technical Committee. Validation of chromatographic methods. Center for Drug Evaluation and Research at the Food and Drug Administration (FDA); 1994. doi: 10.1002/9781118147009.ch15

  24. Baum CL, Selhub J, Rosenberg IH. The hydrolysis of nicotinamide adenine dinucleotide by brush border membranes of rat intestine. Biochem J 1982;204:203–7. doi: 10.1042/bj2040203

  25. Yamashita H, Hirakura Y, Yuda M, Teramura T, Terada K. Detection of cocrystal formation based on binary phase diagrams using thermal analysis. Pharm Res 2013; 30(1): 70–80. doi: 10.1007/s11095-012-0850-1

  26. Oh JH, McCurdy AR, Clark S, Swanson BG. Characterization and thermal stability of polymorphic forms of synthesized tristearin. J Food Sci 2002; 67(8): 2911–7. doi: 10.1111/j.1365-2621.2002.tb08837.x

  27. Felton LA, Yang J, Shah K, Omidian H, Rocca JG. A rapid technique to evaluate the oxidative stability of a model drug. Drug Dev Ind Pharm 2007; 33(6): 683–9. doi: 10.1080/03639040601012890

  28. Goud NR, Gangavaram S, Suresh K, Pal S, Manjunatha SG, Nambiar S, et al. Novel furosemide cocrystals and selection of high solubility drug forms. J Pharm Sci 2012; 101(2): 664–80. doi: 10.1002/jps.22805

  29. Beyers H, Malan SF, Van Der Watt JG, De Villiers MM. Structure-solubility relationship and thermal decomposition of furosemide. Drug Dev Ind Pharm. 2000; 26(10): 1077–83. doi: 10.1081/DDC-100100271

  30. WHO. International pharmacopoeia. 5th ed. 2015. doi: 10.1371/journal.pone.0073560

How to Cite
Campbell M, Jones D, Andrews G, Li S. Understanding the physicochemical properties and degradation kinetics of nicotinamide riboside, a promising vitamin B<sub>3</sub&gt;nutritional supplement. fnr [Internet]. 2019Nov.21 [cited 2019Dec.6];630. Available from: https://foodandnutritionresearch.net/index.php/fnr/article/view/3419
Original Articles