(T1030-08-48) A Search for Novel, Crystalline Nicotine Salts and Cocrystals

Purpose: Salts of nicotine have been described in the literature^1,2 and have been used in consumer products such as pesticides, nicotine replacement therapy (NRT) products (ex., Nicorette^® gum), and electronic cigarettes. Solid state forms including cocrystals, for pharmaceutical applications, have been reported in the literature.³ The use of crystalline nicotine salts or cocrystals in consumer products may have potential advantages such as imparting chemical stability, extending shelf life, and affording manufacturing ease in terms of material handling. Pure nicotine as a neat liquid would no longer need to be handled. The purpose of this study was to search for novel, crystalline forms of nicotine in order to find new materials with better physical properties than were available from commercially available sources, such as nicotine ditartrate dihydrate and nicotine polacrilex. Such crystalline salts or cocrystals, would represent new materials for potential use in nicotine lozenges, moist tobacco, snus, and electronic cigarettes.

Methods: Tobacco-derived (S)-nicotine was sourced from Siegfried, Ltd (Zofingen, Switzerland) as the naturally occurring (S)-enantiomer. The organic acids and coformers were commercially available. Nicotine was combined with commercially available organic acids and coformers using crystallization: (1) from neat nicotine, (2) from organic solvents and water, (3) from freeze dried solids/solvent maturation, (4) by ball-mill grinding, (5) by thermally mediated crystallization, and (6) by gum/oil maturation.

Results: The study produced 13 crystalline nicotine salts; four salts (mucate; 2,3-dihydrozybenzoate; 3,5-dihydroxybenzoate anhydrate and dihydrate) were novel and had not been previously reported. No nicotine cocrystals were obtained in this study. Successful crystallization methods included: (1) Crystallization from neat nicotine, (2) Crystallization from acetone, (3) Freeze-drying and IPA maturation, and (4) Gum/oil maturation. The preparation of these salts were easily scaled up (~5 g) by crystallization from THF, except for mucate (neat nicotine) and 2,3-dihydroxybenzoate (EtOH). All salts were characterized by NMR, DSC, TGA, PLM, and GVS. Because of their good solid-state properties (high mp and low hygroscopicity), testing suggests that either gentisate; 2,3-dihydroxybenzoate; xinafoate; or N-acetyl-4-aminosalicylate nicotine salt may provide alternatives for an analytical reference standard for USP nicotine analysis than the prescribed (S)-nicotine ditartrate dihydrate (1.4% weight gain, 0 to 90% RH GVS isotherm). Four nicotine salts (4-acetamidobenzoate; gentisate; salicylate; 3,5-dihydroxybenzoate (anhydrate)) were produced with morphology acceptable for structure elucidation by single crystal X-ray diffraction (SCXRD) which confirmed the 1:1 nicotine: acid stoichiometry. A single crystal X-ray structure was obtained for the anhydrate form of nicotine 3,5-dihydroxybenzoate. The X-ray structure was of sufficient resolution (with an absolute structure parameter (Flack parameter) of 0.02(7)) to assign the absolute stereochemistry of nicotine as the (S) enantiomer, which is the naturally occurring stereoisomer in tobacco. DSC and TGA thermograms were obtained.

Conclusion: A salt and cocrystal screen was initiated in which 37 organic acids and 10 coformers were investigated for crystalline nicotine salt or cocrystal formation. The search resulted in 13 crystalline nicotine salts which were characterized using solid-state methods. . No nicotine cocrystals were obtained in this study. Four novel, crystalline nicotine salt forms were discovered. One salt, the novel nicotine 2,3-dihydroxybenzoate, had promising solid-state properties and could be used in consumer products and as a nicotine analytical reference standard for USP Monograph testing. The single crystal X-ray structure of the novel nicotine 3,5-dihydroxybenzoate (anhydrate) had a unique crystal packing arrangement and was of sufficient resolution to indicate that the nicotine used in this study possessed the (S) configuration.

References: 1. Perfetti TA. Structural study of nicotine salts. Beiträge zur Tabakforschung. 1983;12(2):43-54.
2. Dull GM, Carr A, Sharp E. Nicotine salts, co-crystals, and salt co-crystal complexes. PCT Int. Appl. (2015). WO 2015183801 A1. Dec 03, 2015.
3. Shilpa C, Sarika N, Neetu K, Shubham W. Co-Crystals: A Review. J Drug Del. Therapy. 2018;8(6-s):350-358.


Table 1. Organic Acids and Coformers--Source and Purity.
(1) Sigma-Aldrich; (2) Fluka; (3) Carbosynth; N/A = Not available


Table 2. Characterization of Crystalline Nicotine Salts.
Abbreviations: CAS Reg. No. = Chemical Abstracts Service Registry Number, Stoich. = Stoichiometry; SCXRD = Single Crystal X-ray Diffraction, THF = Tetrahydrofuran, DSC = Differential Scanning Calorimetry, TGA = Thermal Gravimetric Analysis, PLM = Polarized Light Microscopy, GVS = Gravimetric Vapor Sorption
* = Novel salt form, ‡ = crystallized from neat nicotine, † = crystallized from EtOH, § = XRPD--form unchanged post GVS
ᶲ = The original preparation produced a solid with unknown true stoichiometry. A 2nd preparation from nicotine (4 eq) and crystallization from EtOH-H2O produced the hemimucate (nicotine:mucic acid (1:0.5)).


Figure 1. The structure of nicotine 3,5-dihydroxybenzoate (anhydrate) and hydrogen bonding in the asymmetric unit (top left) and crystal packing -- nicotine in green, acid in blue (right). DSC and TGA thermograms of nicotine 3,5-dihydroxybenzoate (anhydrate) (bottom).