Nicotine Refined: Crystal Engineering of (S)-Nicotinium Malate Salts

Abstract

Nicotine, a widely consumed, yet considered toxic, active pharmaceutical ingredient for recreational use, is known to rapidly deteriorate into unwanted and potentially harmful side products. Crystallization with salt formers transforms the unstable oil into solids with tunable properties. However, previously reported salts and co-crystals are not necessarily safe for human consumption, with several containing heavily halogenated coformers. When combined with malic acid, a generally recognized as safe (GRAS) compound, the four resulting crystalline solids exhibited melting points as high as 122 °C and spanned a range of ∼30 °C. The nicotine-based materials also possessed improved degradation properties. A detailed analysis of the crystal packing and thermodynamic properties provides context for the observed properties.

Transforming liquid nicotine into a stable solid through crystallization with orotic acid

“…Upon heating to approximately 135 °C, nicotinium orotate hemihydrate melts into an amorphous material similar to other previously reported salts. 17,24 The salt had an observable melting point range of 132–135 °C on the digital melting point apparatus, while an endothermic peak was observed at 135.5 °C via DSC. The enthalpy of fusion was determined to be 26.24 kJ mol −1 (Table 2).…”

“…In the nicotinium malate salts, melting points determined via differential scanning calorimetry were observed as ranging from 93.4–122.2 °C, with enthalpies of fusion ranging from 11.22 kJ mol −1 to 18.62 kJ mol −1 . 24 Meanwhile, the nicotine co-crystals possessed melting points ranging between 54 °C to 92 °C, with values ranging from 24.3 kJ mol −1 to 37.9 kJ mol −1 . Nicotinium orotate hemihydrate has a higher melting point than any of the four nicotinium malate salts as well as the nicotine containing co-crystals.…”

“…As observed in the nicotinium malate salts, each salt possesses unique thermal properties, even among polymorphs and similar salts created using only different enantiomers. 24 Understanding the thermal properties of such crystalline systems can be useful in rationally designing and engineering similar materials in the future. 31 The melting point was determined by a digital melting point apparatus, as well as by differential scanning calorimetry (DSC).…”

“…22,23 Previously, malic acids were investigated for their ability to isolate nicotine in the solid-state through crystal engineering. 24 In this work, orotic acid, formerly known as vitamin B13, was selected as the salt former of interest. 24 Orotic acid is a naturally occurring compound that is often used as a supplement and may possess health benefits, such as improved heart health (Fig.…”

“…24 In this work, orotic acid, formerly known as vitamin B13, was selected as the salt former of interest. 24 Orotic acid is a naturally occurring compound that is often used as a supplement and may possess health benefits, such as improved heart health (Fig. 1).…”