WO2024087843A1

WO2024087843A1 - Chiral functionalized modified mof adsorbent, preparation thereof, and application thereof in nicotine enantiomer resolution

Info

Publication number: WO2024087843A1
Application number: PCT/CN2023/114912
Authority: WO
Inventors: 黄艳; 周欣; 赵世兴; 张博; 何骏峰; 王睿
Original assignee: 广州华芳烟用香精有限公司; 华南理工大学
Priority date: 2022-10-25
Filing date: 2023-08-25
Publication date: 2024-05-02
Also published as: CN115678026B; CN115678026A; LU507495B1

Abstract

Disclosed are a chiral functionalized modified MOF adsorbent, the preparation thereof, and an application thereof in nicotine enantiomer resolution. The present invention introduces chiral small molecules into a secondary structural unit of a non-chiral MOF Zr-BTC to construct a chiral recognition environment, and prepares a chiral functionalized modified adsorption material, having a structural formula L@Zr-BTC (where L = chiral small molecules with carboxyl). At normal temperature and normal pressure, such a material can selectively adsorb and separate racemic nicotine, allowing for optically pure nicotine enantiomer production at low cost and with a simple process, and providing a new theoretical basis and application direction for the efficient separation of enantiomers of nitrogen-containing biheterocyclic chiral drugs such as nicotine at normal temperature.

Description

A chiral functionalized modified MOFs adsorbent and its preparation and application in nicotine enantiomer separation

Technical Field

The invention belongs to the field of enantiomer adsorption separation and chemical separation, and specifically relates to a chiral functionalized modified MOFs adsorbent and its preparation and application in nicotine enantiomer separation.

Background technique

Preliminary clinical studies have shown that nicotine is an acetylcholine receptor agonist that can enhance the activity of the cholinergic system and is a potential drug for the treatment of cognitive dysfunction, Alzheimer's disease, schizophrenia and other diseases. The psychoactive activity of (S)-nicotine is much higher than that of (R)-nicotine (Barreto G E, Iarkov A and Moran V E. Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson's disease [J]. Frontiers in aging neuroscience, 2015, 6: 340-340.). Currently, the (S)-nicotine on the market is mainly extracted from natural plants, and the purification steps are complicated and it is difficult to completely remove harmful impurities. In addition, its natural sources are regulated by governments in countries around the world, so clinical research is still subject to certain restrictions. In contrast, synthetic nicotine has the advantages of high purity and few by-products, but the product is usually a racemate, which requires enantiomer separation to meet the needs of clinical research. The development of efficient nicotine enantiomer separation technology will provide valuable high-purity chiral drug support for the treatment of mental illnesses such as Alzheimer's disease.

At present, the method for splitting nicotine enantiomers mostly adopts the recrystallization method, and the chemical splitting agent is a tartaric acid series, such as L-(-)-dibenzoyltartaric acid, L-(-)-di-p-methylbenzoyltartaric acid, L-(-)-di-p-methoxybenzoyltartaric acid (CN 111187250 A; CN 111527077 A; CN 111004212 A). This method has the disadvantages of single splitting agent, high solvent consumption, high evaporation energy consumption, and cumbersome operation steps. In comparison, enantiomeric splitting based on adsorption technology can be operated at room temperature and pressure conditions to obtain high-purity products, with the advantages of high efficiency and energy saving, and chiral adsorbents are the core of adsorption splitting technology. Metal-organic framework materials MOFs have the advantages of high porosity, large specific surface area, adjustable pore structure and surface chemistry. Introducing a chiral environment into the pores of achiral MOFs that do not have chiral recognition ability can give them the ability to recognize and separate chiral molecules. However, in the technical field of nicotine enantiomer separation, there has been no chiral adsorption separation material that can achieve efficient enantiomer separation of nicotine and such nitrogen-containing bicyclic racemic substances at room temperature, which is a bottleneck problem restricting the practical application of adsorption separation technology in this technical field.

Summary of the invention

In view of the bottleneck problem existing in the technical field of nicotine enantiomer adsorption separation, the primary purpose of the present invention is to provide a method for preparing a chiral functionalized modified MOFs adsorbent.

The chiral functionalized modified MOFs adsorbent obtained by the method of the present invention can realize the separation of nicotine enantiomers, realize the selective and efficient adsorption and removal of (S)-nicotine and (R)-nicotine enantiomers respectively, and efficiently prepare (R)-nicotine or (S)-nicotine with high optical purity. The chiral functionalized modified MOFs adsorbent obtained by the present invention can realize the production of optically pure nicotine enantiomers with low cost and simple process, and provide a new theoretical basis and application direction for the efficient separation of enantiomers of nitrogen-containing biheterocyclic chiral drugs such as nicotine at room temperature.

Another object of the present invention is to provide a chiral functionalized modified MOFs adsorbent prepared by the above method.

Another object of the present invention is to provide the use of the chiral functionalized modified MOFs adsorbent in the separation of nicotine enantiomers.

The purpose of the present invention is achieved through the following technical solutions:

A method for preparing a chiral functionalized modified MOFs adsorbent comprises the following steps:

(1) adding a metal salt and trimesic acid (H ₃ BTC) into a solvent, reacting at 100-120° C. for 1-3 days, collecting a white solid by centrifugation, and washing to obtain achiral Zr-BTC;

(2) Adding achiral Zr-BTC and a chiral small molecule with a carboxyl group into a solvent, reacting at 40-65° C. for 1-2 days, collecting the white solid by centrifugation, and washing to obtain a chiral small molecule @Zr-BTC material.

Preferably, the metal salt in step (1) is at least one of zirconium oxychloride octahydrate (ZrOCl ₂ ·8H ₂ O) and zirconium chloride (ZrCl ₄ ).

Preferably, the molar ratio of the metal salt to trimesic acid in step (1) is (2.5-3.5):1.

Preferably, the solvent in step (1) is a mixture of formic acid and N,N-dimethylformamide (DMF) in a volume ratio of (0.7-1.2):1.

Preferably, in step (1), the ratio of the metal salt to the solvent is 15-17 mg:1 mL.

Preferably, the centrifugation conditions in steps (1) and (2) are both 8000-12000 rpm for 3-5 min.

Preferably, the washing in step (1) is to soak the white solid in a solvent, wherein the solvent is at least one of DMF and acetone; more preferably, the pore-blocking impurities are first removed by soaking in DMF, and then the DMF is exchanged by soaking in acetone with a greater polarity; the washing is to remove excess metal or ligand inside the MOF pores, and to perform solvent exchange, replacing the high-boiling-point solvent with a low-boiling-point solvent, so as to facilitate subsequent drying.

Preferably, the washing in steps (1) and (2) is followed by drying, specifically drying at room temperature to 60° C. for 8 to 24 hours, more preferably drying under vacuum conditions.

Preferably, the molar ratio of the achiral Zr-BTC to the chiral small molecule with a carboxyl group in step (2) is 1:(10-120); more preferably 1:(40-80).

Preferably, the chiral small molecule with a carboxyl group in step (2) is at least one of L-tartaric acid, L-mandelic acid, L-aspartic acid, L-alanine and L-serine; more preferably at least one of L-tartaric acid and L-mandelic acid.

Preferably, in step (2), the ratio of the achiral Zr-BTC to the solvent is 2-3 mg:1 mL; and the solvent is at least one of water and DMF.

Preferably, the washing in step (2) is to wash the white solid by immersing it in a solvent, and the solvent is at least one of water, DMF and acetone; more preferably, the white solid is first washed by immersing it in at least one of water and DMF, and then washed by immersing it in acetone.

A chiral functionalized modified MOFs adsorbent prepared by the above preparation method.

The above-mentioned chiral functionalized modified MOFs adsorbent is used for the separation of nicotine enantiomers.

Preferably, the application is: adding the chiral functionalized modified MOFs adsorbent to a racemic nicotine solution, stirring and adsorbing at room temperature, and removing the chiral functionalized modified MOFs adsorbent to obtain a target nicotine enantiomer solution.

Preferably, the concentration of the racemic nicotine solution is 0.2-1.5 mg/mL; and the mass ratio of the chiral functionalized modified MOFs adsorbent to nicotine is 1.5-13:1.

Preferably, the time of adsorption under stirring at room temperature is 18 to 24 hours.

Compared with the prior art, the present invention has the following advantages and beneficial effects:

(1) The synthesis process is simple, the ligand is inexpensive, and it is easy to scale up the synthesis.

(2) For the first time, chiral MOFs materials that can be used for the adsorption and separation of racemic nicotine were prepared. They can adsorb and separate nicotine enantiomers at room temperature and pressure.

(3) The chiral environment inside the pores can be precisely controlled to further meet the adsorption and separation requirements of the adsorbent for different optically active enantiomers.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a hydrogen nuclear magnetic resonance spectrum of the chiral adsorption material prepared in Examples 1-6.

FIG. 2 is an X-ray powder diffraction characterization diagram of the chiral adsorption materials prepared in Examples 1 and 6.

FIG3 shows the adsorption performance of the chiral adsorption materials prepared in Examples 1 and 6 for nicotine enantiomers in liquid phase.

Figure 4 shows the adsorption performance of L-Tar@UiO-66- _NH2 prepared in Comparative Example 1 on racemic nicotine.

Detailed ways

The present invention is further described in detail below in conjunction with examples and drawings, but the embodiments of the present invention are not limited thereto.

If no specific conditions are specified in the examples of the present invention, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. All raw materials, reagents, etc., whose manufacturers are not specified, are conventional products that can be purchased commercially.

Example 1

210 mg of H ₃ BTC and 970 mg of ZrOCl ₂ ·8H ₂ O were weighed and added to a 100 mL glass bottle filled with DMF/formic acid (30 mL/30 mL), sealed, and heated in an oven at 100°C for 3 days. The obtained white solid was collected by centrifugation (10000 rpm, 3 min). The solid was first soaked and washed three times (8 hours each time) with DMF (60 mL each time), and then soaked and washed three times (8 hours each time) with acetone (60 mL each time). Finally, the product was transferred to a vacuum drying oven and dried overnight at room temperature to obtain activated Zr-BTC. 0.1 g of activated Zr-BTC and 0.9 g of L-tartaric acid were added to a glass bottle filled with 40 mL of water. The mixture was stirred in a water bath at 60°C for 24 h. Centrifugation (10000 rpm, 5 min) obtained a white solid. The solid was first washed by soaking in water (60 mL each time) for three times (8 hours each time), and then by soaking in acetone (60 mL each time) for three times (8 hours each time). Finally, the sample was dried overnight at room temperature, and the obtained white solid was recorded as L-Tar@Zr-BTC.

2 mL of racemic nicotine solution with concentrations of 0.5, 0.8, and 1 mg·mL ^-1 was prepared, and 5 mg of L-Tar@Zr-BTC adsorbent was added respectively. The mixture was stirred at room temperature for 24 h. The concentrations before and after adsorption were detected and calculated by chiral HPLC.

Example 2

Weigh 210 mg of H ₃ BTC and 970 mg of ZrOCl ₂ ·8H ₂ O, add to a 100 mL glass bottle filled with DMF/formic acid (30 mL/30 mL), seal, and heat in a 100 ° C oven for 3 days. The obtained white solid is collected by centrifugation (10000 rpm, 3 min). The solid is first soaked and washed three times (8 hours each time) with DMF (60 mL each time), and then soaked and washed three times (8 hours each time) with acetone (60 mL each time). Finally, the product is transferred to a vacuum drying oven and dried overnight at room temperature to obtain activated Zr-BTC. 0.1 g of activated Zr-BTC and 0.9 g of L-tartaric acid are added to a glass bottle filled with 40 mL of water. The mixture is stirred in a water bath at 45 ° C for 24 h. Centrifugation (10000 rpm, 5 min) obtains a white solid. The solid was first washed by soaking in water (60 mL each time) for three times (8 hours each time), and then by soaking in acetone (60 mL each time) for three times (8 hours each time). Finally, the sample was dried overnight at room temperature, and the obtained white solid was recorded as L-Tar@Zr-BTC.

Example 3

Weigh 210 mg of H ₃ BTC and 970 mg of ZrOCl ₂ ·8H ₂ O, add to a 100 mL glass bottle filled with DMF/formic acid (30 mL/30 mL), seal, and heat in a 100 ° C oven for 3 days. The obtained white solid is collected by centrifugation (10000 rpm, 3 min). The solid is first soaked and washed three times (8 hours each time) with DMF (60 mL each time), and then soaked and washed three times (8 hours each time) with acetone (60 mL each time). Finally, the product is transferred to a vacuum drying oven and dried overnight at room temperature to obtain activated Zr-BTC. 0.1 g of activated Zr-BTC and 0.9 g of L-tartaric acid are added to a glass bottle filled with 40 mL of water. The mixture is stirred in a water bath at 45 ° C for 48 h. Centrifugation (10000 rpm, 5 min) obtains a white solid. The solid was first washed by soaking in water (60 mL each time) for three times (8 hours each time), and then by soaking in acetone (60 mL each time) for three times (8 hours each time). Finally, the sample was dried overnight at room temperature, and the obtained white solid was recorded as L-Tar@Zr-BTC.

Example 4

Weigh 210 mg of H ₃ BTC and 970 mg of ZrOCl ₂ ·8H ₂ O, add to a 100 mL glass bottle filled with DMF/formic acid (30 mL/30 mL), seal, and heat in a 100 ° C oven for 3 days. The obtained white solid is collected by centrifugation (10000 rpm, 3 min). The solid is first soaked and washed three times (8 hours each time) with DMF (60 mL each time), and then soaked and washed three times (8 hours each time) with acetone (60 mL each time). Finally, the product is transferred to a vacuum drying oven and dried overnight at room temperature to obtain activated Zr-BTC. 0.1 g of activated Zr-BTC and 0.9 g of L-tartaric acid are added to a glass bottle filled with 40 mL of water. The mixture is stirred in a water bath at 40 ° C for 24 h. Centrifugation (10000 rpm, 5 min) obtains a white solid. The solid was first washed by soaking in water (60 mL each time) for three times (8 hours each time), and then by soaking in acetone (60 mL each time) for three times (8 hours each time). Finally, the sample was dried overnight at room temperature, and the obtained white solid was recorded as L-Tar@Zr-BTC.

Example 5

210 mg of H ₃ BTC and 970 mg of ZrOCl ₂ ·8H ₂ O were weighed and added to a 100 mL glass bottle filled with DMF/formic acid (30 mL/30 mL), sealed, and heated in an oven at 100°C for 3 days. The obtained white solid was collected by centrifugation (10000 rpm, 3 min). The solid was first washed by soaking in DMF (60 mL each time) for three times (8 hours each time), and then by soaking in acetone (60 mL each time) for three times. (8 hours each time). Finally, the product was transferred to a vacuum drying oven and dried overnight at room temperature to obtain activated Zr-BTC. 0.2g of activated Zr-BTC and 0.9g of L-tartaric acid were added to a glass bottle containing 40mL of water. The mixture was stirred in a water bath at 45°C for 24h. Centrifugation (10000rpm, 5min) obtained a white solid. First, the solid was soaked and washed three times (8 hours each time) with water (60mL each time), and then soaked and washed three times (8 hours each time) with acetone (60mL each time). Finally, the sample was dried overnight at room temperature, and the obtained white solid was recorded as L-Tar@Zr-BTC.

Example 6

231 mg of H ₃ BTC and 1.06 g of ZrOCl ₂ ·8H ₂ O were weighed and added to a 100 mL glass bottle filled with DMF/formic acid (35 mL/35 mL), sealed, and heated in an oven at 120°C for 3 days. The obtained white solid was collected by centrifugation (8000 rpm, 5 min). The solid was first soaked and washed three times (8 hours each time) with DMF (60 mL each time), and then soaked and washed three times (8 hours each time) with acetone (60 mL each time). Finally, the product was transferred to a vacuum drying oven and dried overnight at 60°C to obtain activated Zr-BTC. 0.1 g of activated Zr-BTC and 0.6 g of L-mandelic acid were added to a glass bottle filled with 40 mL of DMF. The mixture was stirred in a water bath at 65°C for 24 h. Centrifugation (8000 rpm, 3 min) obtained a white solid. The solid was first washed by soaking in water (60 mL each time) for three times (8 hours each time), and then by soaking in acetone (60 mL each time) for three times (8 hours each time). Finally, the sample was dried at 60°C overnight, and the obtained white solid was recorded as L-Man@Zr-BTC.

2 mL of racemic nicotine solution with concentrations of 0.4, 0.6, 0.8, 1.0, and 1.2 mg·mL ^-1 was prepared, and 5 mg of L-Tar@Zr-BTC adsorbent was added respectively. The mixture was stirred at room temperature for 24 h. The concentrations before and after adsorption were detected and calculated by chiral HPLC.

Comparative Example 1

Dissolve 0.192g 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 0.043g N-hydroxysuccinimide sulfonic acid sodium salt and 0.15g L-tartaric acid in 20mL 0.1mol/L MES buffer solution and stir at room temperature for 1h. Add 0.175g UiO-66-NH ₂ and stir at room temperature for 5 days. Collect the solid by suction filtration, wash with water several times, and finally dry under vacuum at 60℃. The obtained solid is recorded as L-Tar@UiO-66-NH ₂ .

Prepare 2 mL of racemic nicotine solution with concentrations of 0.3 and 0.6 mg mL ^-1 , respectively, and add 5 mg The L-Tar@UiO-66-NH ₂ adsorbent was stirred at room temperature for 24 h, and the concentrations before and after adsorption were detected and calculated using chiral high performance liquid chromatography.

Structural characterization and performance determination of adsorbent materials

(a), (b), (c), (d), (e), and (f) in Figure 1 are ¹ H NMR spectra of L-Tar@Zr-BTC and L-Man@Zr-BTC in Examples 1, 2, 3, 4, 5, and 6, respectively. Taking (a) in Figure 1 as an example, the chemical shifts of the trimesic acid ligand and the formic acid group on the metal cluster of Zr-BTC are 7.95ppm and 8.01ppm, respectively. The single absorption peak of L-Tar at 3.85ppm originates from the hydrogen atoms on its two chiral carbons. Due to the electron-withdrawing effect induced by the adjacent hydroxyl and carboxyl groups, the electron cloud density around the hydrogen atom decreases, and the shielding effect is weakened, so the chemical shift increases. Compared with Zr-BTC, the absorption peak with a chemical shift of 8.01ppm in the ^1H NMR spectrum of L-Tar@Zr-BTC almost completely disappeared, and the hydrogen absorption peak of L-Tar appeared at 3.85ppm, indicating that L-tartaric acid successfully replaced the formic acid group on the Zr-BTC metal cluster. Similarly, it can be known that L-mandelic acid is also modified into MOF by replacing the formic acid group on the Zr-BTC metal cluster. According to the ratio of the absorption peak intensity of the chiral small molecule and BTC, the modification of the chiral small molecule can be inferred, that is, each _Zr6 secondary structural unit of L-Tar@Zr-BTC in Examples 1-5 is modified with 2.26, 1.86, 1.77, 1.83, and 1.71 L-Tar chiral molecules, respectively, and each _Zr6 secondary structural unit of L-Man@Zr-BTC in Example 6 is modified with 3.48 L-Man chiral molecules.

Figure 2 is the PXRD spectra of L-Tar@Zr-BTC and L-Man@Zr-BTC prepared in Examples 1 and 6. As can be seen from the figure, the experimentally prepared Zr-BTC is almost completely consistent with the spectrum obtained by simulation, indicating that Zr-BTC was successfully prepared and has a high purity. The characteristic peaks of the synthesized L-Tar@Zr-BTC and L-Man@Zr-BTC are similar to those of Zr-BTC, but the main peaks are blue-shifted, which indicates that L-Tar@Zr-BTC and L-Man@Zr-BTC retain the crystal structure of the raw materials, but the introduction of chiral small molecules slightly expands the interplanar spacing of Zr-BTC.

Figure 3 shows the adsorption performance of L-Tar@Zr-BTC in Example 1 and L-Man@Zr-BTC in Example 6 on racemic nicotine. As can be seen from the figure, the introduction of chiral sites gives Zr-BTC chiral selectivity, and chiral molecules of different configurations can preferentially adsorb different nicotine enantiomers. For example, L-tartaric acid ((2R,3R)-tartaric acid) preferentially adsorbs (S)-nicotine, and L-mandelic acid ((S)-mandelic acid) preferentially adsorbs (S)-nicotine. Attached (R)-nicotine. Compared with L-Tar@Zr-BTC, the adsorption amount of L-Man@Zr-BTC is reduced, but the adsorption selectivity is slightly improved, which is related to the properties of the chiral ligand chain. The flexible chain of L-Tar divides the pore area, enhances the confinement effect of the pore on nicotine, and increases the adsorption capacity of nicotine; the rigid aromatic ring structure of L-Man enhances the steric effect and π-π conjugation effect with nicotine. According to the chiral "three-point recognition model", it can be seen that the chiral selectivity of the material is further improved.

Figure 4 shows the adsorption performance of L-Tar@UiO-66- _NH2 prepared in Comparative Example 1 on racemic nicotine. As can be seen from the figure, the material has almost the same adsorption amount of nicotine for the two configurations, indicating that it has no adsorption selectivity for nicotine. Combining Figures 3 and 4, it can be seen that the spatial structure of MOF plays an important role in the recognition of chiral sites. The pore size of Zr-BTC is more matched with the size of nicotine molecules, and the confined environment further amplifies the enantiomeric recognition effect of the chiral microenvironment.

The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

A method for preparing a chiral functionalized modified MOFs adsorbent, characterized in that it comprises the following steps:

(1) adding a metal salt and trimesic acid to a solvent, reacting at 100-120° C. for 1-3 days, collecting a white solid by centrifugation, and washing to obtain achiral Zr-BTC;

(2) adding achiral Zr-BTC and a chiral small molecule with a carboxyl group into a solvent, reacting at 40-65° C. for 1-2 days, collecting the white solid by centrifugation, and washing to obtain a chiral small molecule @Zr-BTC material;

The solvent in step (1) is a mixture of formic acid and N,N-dimethylformamide in a volume ratio of (0.7-1.2):1;

The chiral small molecule with a carboxyl group in step (2) is at least one of L-tartaric acid and L-mandelic acid.
The method for preparing a chiral functionalized modified MOFs adsorbent according to claim 1 is characterized in that:

The molar ratio of the achiral Zr-BTC to the chiral small molecule with a carboxyl group in step (2) is 1:(10-120).
The method for preparing a chiral functionalized modified MOFs adsorbent according to claim 1, characterized in that the metal salt in step (1) is at least one of zirconium oxychloride octahydrate and zirconium chloride;

The molar ratio of the metal salt to trimesic acid in step (1) is (2.5-3.5):1.
The method for preparing a chiral functionalized modified MOFs adsorbent according to claim 1, characterized in that the ratio of the metal salt to the solvent in step (1) is 15-17 mg:1 mL;

In step (2), the ratio of the achiral Zr-BTC to the solvent is 2-3 mg:1 mL; the solvent is at least one of water and DMF.
The method for preparing a chiral functionalized modified MOFs adsorbent according to claim 1, characterized in that the centrifugation conditions in steps (1) and (2) are both 8000-12000 rpm for 3-5 min;

The washing in step (1) is to soak and wash the white solid with a solvent, wherein the solvent is at least one of DMF and acetone;

The washing in step (2) is to soak and wash the white solid with a solvent, wherein the solvent is at least one of water, DMF and acetone;

After washing in steps (1) and (2), the mixture is dried, specifically at room temperature to 60° C. for 8 to 24 hours.
A chiral functionalized modified MOFs adsorbent prepared by the preparation method according to any one of claims 1 to 5.
The use of a chiral functionalized modified MOFs adsorbent as described in claim 6 in the separation of nicotine enantiomers.
The use of a chiral functionalized modified MOFs adsorbent in the resolution of nicotine enantiomers according to claim 7 is characterized in that the chiral functionalized modified MOFs adsorbent according to claim 7 is added to a racemic nicotine solution, adsorbed by stirring at room temperature, and the chiral functionalized modified MOFs adsorbent is removed to obtain a target nicotine enantiomer solution.
According to claim 8, the use of a chiral functionalized modified MOFs adsorbent in the resolution of nicotine enantiomers is characterized in that the concentration of the racemic nicotine solution is 0.2 to 1.5 mg/mL; the mass ratio of the chiral functionalized modified MOFs adsorbent to nicotine is 1.5 to 13:1; and the time of the adsorption under room temperature stirring is 18 to 24 hours.