New Crystalline Salts of Nicotinamide Riboside as Food Additives

Abstract

NR⁺ is a highly effective vitamin B₃ type supplement due to its unique ability to replenish NAD⁺ levels. While NR⁺ chloride is already on the market as a nutritional supplement, its synthesis is challenging, expensive, and low yielding, making it cumbersome for large-scale industrial production. Here we report the novel crystalline NR⁺ salts, d/l/dl-hydrogen tartrate and d/l/dl-hydrogen malate. Their high-yielding, one-pot manufacture does not require specific equipment and is suitable for multi-ton scale production. These new NR⁺ salts seem ideal for nutritional applications due to their bio-equivalence compared to the approved NR⁺ chloride. In addition, the crystal structures of all stereoisomers of NR⁺ hydrogen tartrate and NR⁺ hydrogen malate and a comparison to the known NR⁺ halogenides are presented.

Keywords: B3 supplement; NR+ salts; crystal structures; nicotinamide riboside; salt screening.

Figure 1

Structures of NAD⁺, NR⁺ and NAM.

Scheme 1

Main approaches for the NR⁺ synthesis. Adapted from Makarov and Migaud [33].

Scheme 2

Adapted from Makarov and Migaud [33].

Scheme 3

Synthesis of new NR⁺ salt via salt metathesis from NR⁺ bromide and triethylammonium salts.

Figure 2

Structural formulas of the crystalline NR⁺ derivatives: nicotinamide-β-d-riboside d-hydrogen tartrate (11), nicotinamide-β-d-riboside l-hydrogen tartrate (12), nicotinamide-β-d-riboside l-hydrogen malate (13), nicotinamide-β-d-riboside d-hydrogen malate (14).

Figure 3

Displacement ellipsoid representations at 50% probability of: 11a (A) obtained by vapor diffusion; 11b (B) and 12 (C) obtained by controlled cooling; 13 (D) and 14 (E) obtained by thermal crystallization and addition of an anti-solvent.

Figure 4

Overlay of the nicotinamide-β-d-riboside cations of 11a, 11b, and 12. The structures were overlayed on atoms O4, C1, and N1 with the help of the program Mercury. [64]

Figure 5

Degradation rate of NR⁺ l-hydrogen malate to NAM as peak area measurement over time at pH 4.5 at different temperatures.

Scheme 4

Improved synthetic route via NR triflate.