Rivastigmine tartrate: uses and Synthesis method

Introduction

Rivastigmine Tartrate (RT) is an acetylcholinesterase inhibitor that reversibly inhibits both the acetylcholinesterase and butyrylcholinesterase enzymes, which is superior in terms of specificity of action and minimal side effects. Rivastigmine tartrate is chemically known as (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate hydrogen-(2R,3R)-tartrate (CASRN: 129101-54-8; empirical formula: C14H22N2O2·C4H6O6). The S-isomer rivastigmine has a considerably higher drug efficacy than the racemate and R-isomer[1].

Synthesis method

The existing method to obtain rivastigmine tartrate in the industry is to salify rivastigmine with L-(+)- tartaric acid. To improve the yield and obtain crystal form with higher crystallinity in industrialized processes, crystallization is employed to separate and purify crude products, which is one of the most commonly used methods for separating active ingredients from the mixture by utilizing different solubilities of components. Because of its relatively high solubility in water, rivastigmine tartrate hardly dissolves in various organic solvents, so a large volume of organic solvent is needed. Thus, cooling crystallization was combined with anti-solvent crystallization to improve the yield and increase the purity, especially the chiral purity of S-isomer.

Uses

RT was the first approved drug to be marketed for Alzheimer's in Switzerland in the year 1997 and then became popular in 80 countries worldwide, including Canada, Europe etc. RT causes minimal interactions when taken with other drugs, especially in elderly individuals who are on different medications for concurrent illnesses, increasing its importance further in the market. Though it is a BCS class 1 drug and has both good solubility and permeability, still its use is limited due to its low bioavailability, poor penetration through BBB, short half-life and gastrointestinal side effects when administered orally. It is freely soluble in various solvents like distilled water, ethanol, acetone, phosphate buffers, etc. It shows an absorption maxima of 263 nm. To solve problems like short half-life, poor penetration across BBB due to the presence of efflux transporters and gastrointestinal disorders, various lipid particulate systems like SLNs and NLC, nanocarriers like polymeric nanoparticles, and nanosponges have been developed[2].

Rivastigmine tartrate is a dual-action cholinesterase inhibitor shown to improve language, cognition, and global functioning in patients with Alzheimer's, likely via increased availability of cerebral acetylcholine. Because cholinergic receptor abnormalities can contribute to the neuropathology of autistic spectrum disorders, rivastigmine tartrate could prove to be an effective therapy for affected children. Testing administered at baseline, 6 weeks, and 12 weeks showed gains in both expressive speech and overall autistic behaviour over baseline. These improvements were statistically significant and supported the hypothesis that treatment with cholinergic-enhancing drugs in autistic spectrum disorders yields positive therapeutic effects.

References

[1] Kefei He. “Study of equilibrium solution and thermodynamic models in correlation with solubility data of rivastigmine tartrate in (H2O + isopropanol), (H2O + ethanol), and (H2O + acetonitrile) binary solvent mixtures.” Journal of Thermal Analysis and Calorimetry 136 2 (2018): 815–832.

[2] Deepshi Arora. “UV Spectrophotometric Method for Quantification of Rivastigmine Tartrate in Simulated Nasal Fluid: Development and Validation.” Biomedical and Pharmacology Journal 11 1 (2021).

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