BIOCOMPATIBLE COLLOIDAL SOLUTION OF SILVER NANOPARTICLES IN NON-AQUEOUS POLAR SOLVENT AND METHOD OF OBTAINING THEREOF

Abstract

The present application relates to colloidal chemistry, specifically to methods of synthesising silver nanoparticle colloids in a non-aqueous solvent, preferably, in dimethyl sulfoxide. In particular these silver nanoparticles have an average size of 12-20 nm and are in a biocompatible colloidal solution.

Claims

1. A biocompatible colloidal solution of silver nanoparticles in a non-aqueous polar solvent, preferably, in dimethyl sulfoxide, characterized in that the solution contains silver nanoparticles, obtained by reducing a silver salt, using a biocompatible reductant, which requires an alkaline medium to reduce silver ions to silver nanoparticles [Ag.sup.0], and the alkaline medium is obtained with tetraalkylammonium hydroxide, and the ingredients are taken in such amount, that allows obtaining nanoparticles with an average size of 12-20 nm, and the resulting colloidal solution is adjusted to neutral pH.

2. The colloid solution of claim 1, wherein ascorbic agent is a biocompatible reducing agent.

3. The colloid solution of claim 1, wherein glycerine is a biocompatible reducing agent.

4. The colloid solution of claim 1, wherein hydrogen peroxide is a biocompatible reducing agent.

5. The colloid solution of claim 1, wherein ethyl alcohol is a biocompatible reducing agent.

6. The colloid solution of claim 1, wherein glucose is a biocompatible reducing agent.

7. The colloid solution of claim 1, wherein tetraethylammonium hydroxide or tetraisopropylammonium hydroxide or tetrabutylammonium hydroxide or tetrapentylammonium hydroxide is tetraalkylammonium hydroxide.

8. The colloid solution of claim 1, wherein silver nitrate (I) is a silver salt.

9. The colloid solution of claim 1, wherein the average size of silver [Ag.sup.0] nanoparticles is within 12-20 nm.

10. A method of obtaining a colloidal solution of silver nanoparticles in a nonaqueous polar solvent, preferably, in dimethyl sulfoxide, of claim 1, characterized in that silver salt is reduced by a biocompatible reducing agent in an alkaline medium when the solution of a silver salt and dimethyl sulfoxide interacts with a biocompatible reductant, which requires an alkaline medium to reduce silver ions to silver nanoparticles [Ag.sup.0], dimethyl sulfoxide and tetraalkyl ammonium hydroxide, and the resulting colloidal solution is then adjusted to neutral pH.

11. The method of claim 10, wherein the resulting colloidal solution is adjusted to neutral pH by adding an organic acid to the resulting colloidal solution.

12. The method of claim 10, wherein ascorbic acid is used as a biocompatible reducing agent.

13. The method of claim 10, wherein glycerine is used as a biocompatible reducing agent.

14. The method of claim 10, wherein hydrogen peroxide is used as a biocompatible reducing agent.

15. The method of claim 10, wherein ethyl alcohol is used as a biocompatible reducing agent.

16. The method of claim 10, wherein glucose is used as a biocompatible reducing agent.

17. The method of claim 10, wherein tetraethylammonium hydroxide or tetraisopropylammonium hydroxide or tetrabutylammonium hydroxide or tetrapentylammonium hydroxide is used as tetraalkylammonium hydroxide.

18. The method of claim 10, wherein silver nitrate (I) is used as a silver salt.

Description

[0032] The invention disclosed herein is illustrated by the following examples of obtaining a biocompatible colloidal solution of silver nanoparticles (NPs) using AA as a reductant or using alternative reductantsglycerine, hydrogen peroxide, ethyl alcohol and glucose, and by the following graphic materials, specifically:

[0033] FIG. 1 shows distribution by solvodynamic size (a) and absorption spectra (b) of colloidal silver NPs synthetized with Et.sub.4NOH (curves 1), Pr.sub.4NOH (curves 2), Bu.sub.4NOH (curves 3) and Pt.sub.4NOH (curves 4). [Ag.sup.0]=210.sup.3 mol/L, [AA]=110.sup.3 mol/L, [OH.sup.]=110.sup.2 mol/L. Cuvette1.0 mm (for this and subsequent distributions), DMSO;

[0034] FIG. 2 shows electron microphotographs of colloidal silver NPs synthetized in Example 1;

[0035] FIG. 3 shows distribution by solvodynamic size (a) and absorption spectra (b) of colloidal silver NPs synthetized with various amounts of Et.sub.4NOH: 510.sup.3 mol/L (curves 1), 110.sup.2 mol/L (curves 2), 1.510.sup.2 mol/L (curves 3), 2 10.sup.2 mol/L (curves 4). [Ag.sup.0]=210.sup.3 mol/L, [AA]=110.sup.3 mol/L, DMSO;

[0036] FIG. 4 shows distribution by solvodynamic size (a) and absorption spectra (b) of colloidal silver NPs synthetized with 110.sup.2 mol/L Et.sub.4NOH and various amounts of AA: 510.sup.4 mol/L (curves 1), 110.sup.3 mol/L (curves 2), 310.sup.3 mol/L (curves 3), 510.sup.3 mol/L (curves 4). [Ag.sup.0]=210.sup.3 mol/L, DMSO;

[0037] FIG. 5 shows distribution by solvodynamic size (a) and absorption spectra (b) of colloidal silver NPs synthetized at 25 C. and exposed to heating at 50 C. following synthesis. Absorption spectra are given for a colloid heated after synthesis to 70 C. (c) and 90 C. (d). [Ag.sup.0]=210.sup.3 mol/L, [AA]=110.sup.3 mol/L, [Et.sub.4NOH]=110.sup.2 mol/L, DMSO;

[0038] FIG. 6 shows changes in distribution of silver NPs by solvodynamic size (a) and colloid absorption spectra (b) exposed to 25 C. Synthesis is carried out at 25 C. [Ag.sup.0]=210.sup.3 mol/L, [AA]=110.sup.3 mol/L, [Et.sub.4NOH]=110.sup.2 mol/L, DMSO;

[0039] FIG. 7 shows absorption spectra for silver NPs, synthetized at 25 C., 40 C., 60 C., 70 C., 90 C. [Ag.sup.0]=210.sup.3 mol/L, [AA]=110.sup.3 mol/L, [Et.sub.4NOH]=110.sup.2 mol/L, DMSO;

[0040] FIG. 8 shows absorption spectra for silver NPs, synthetized in DMSO at 25 C. using 0.5% glycerine (curve 1), 0.1% glucose (curve 2), 0.1% ethanol (curve 3), 0.5% H.sub.2O.sub.2 (curve 4), 0.5% H.sub.2O.sub.2 (curve 5) and 0.75% H.sub.2O.sub.2 (curve 6). [Ag.sup.0]=210.sup.3 mol/L, [Et.sub.4NOH]=110.sup.2 mol/L;

[0041] FIG. 9 shows raster electron microphotographs of silver NPs, synthetized in Example No. 21;

[0042] Graphic materials, which illustrate the invention disclosed herein, and an example of the resulting biocompatible colloidal solution of silver nanoparticles and the method obtaining thereof are not intended to restrict the scope of claims thereto, but explain the essence of the invention only.

[0043] In the first panel of examples, a biocompatible colloidal solution of silver NPs was obtained using ascorbic acid as a reductant and tetraalkylammonium hydroxides, having various alkyl groups, to form an alkaline medium.

[0044] Example No. 1: Obtaining a biocompatible colloidal solution of silver NPs using tetraethylammonium hydroxide. Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous hydroxide tetraethylammonium (Et.sub.4NOH) solution and 0.1 ml of 0.1 mol/L of AA solution in DMSO were added to 4.8 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added under vigorous stirring. This forms a solution of silver NPs containing [Ag.sup.0]=210.sup.3 mol/L. Distribution of silver NPs by solvodynamic size (SDS) and colloid absorption spectrum are demonstrated by curves on FIG. 1a and FIG. 1b, respectively.

[0045] For this and subsequent panels of examples, a standard magnetic mixer, 300 rpm, was used for stirring. NPs are synthetized at a room temperature in the air.

[0046] Example No. 2: Obtaining a biocompatible colloidal solution of silver NPs using tetraisopropylammonium hydroxide. Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraisopropylammonium hydroxide (Pr.sub.4NOH) solution and 0.1 ml of 0.1 mol/L AA solution in DMSO were added to 4.8 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs containing [Ag.sup.0]=210.sup.3 mol/L. Distribution of silver NPs by SDS and colloid absorption spectrum are demonstrated by curves 2 on FIG. 1a and FIG. 1b, respectively.

[0047] Example No. 3: Obtaining a biocompatible colloidal solution of silver NPs using tetrabutylammonium hydroxide. Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetrabutylammonium hydroxide (Bt.sub.4NOH) solution and 0.1 ml of 0.1 mol/L AA solution in DMSO were added to 4.8 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs containing [Ag.sup.0]=210.sup.3 mol/L. Distribution of silver NPs by SDS and colloid absorption spectrum are demonstrated by curves 3 on FIG. 1a and FIG. 1b, respectively.

[0048] Example No. 4: Obtaining a biocompatible colloidal solution of silver NPs using tetrapentylammonium hydroxide. Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetrapentylammonium hydroxide (Pt.sub.4NOH) solution and 0.1 ml of 0.1 mol/L AA solution in DMSO were added to 4.8 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs containing [Ag.sup.0]=210.sup.3 mol/L. Distribution of silver NPs by SDS and colloid absorption spectrum are demonstrated by curves 4 on FIG. 1a and FIG. 1b, respectively.

[0049] As shown in FIG. 1, distribution of silver NPs, obtained using various organic alkali, and absorption spectra thereof depends on the nature of organic alkali. Silver NPs of smallest size are formed in the presence of tetraethylammonium hydroxide. Therefore, this compound was used as an organic base for subsequent syntheses.

[0050] FIG. 2 shows raster (FIG. 1a) and transmission (section 1b) electron microphotographs of Ag NPs, obtained by this method. The data shows, that the average size of NPs is 12-20 nm, that is consistent with findings of dynamic light scattering spectroscopy.

[0051] The second panel of examples was intended to select optimal concentration of tetraethylammonium hydroxide to obtain silver NPs, having maximum stability and minimum SDS.

[0052] Example No. 5: Two separate solutions were prepared first as described below. 0.05 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.1 ml of 0.1 mol/L AA solution in DMSO were added to 4.8 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs, containing [Ag.sup.0]=210.sup.3 mol/L. Distribution of silver NPs by SDS and colloid absorption spectrum are demonstrated by curves 1 on FIG. 3a and FIG. 3b, respectively.

[0053] Example No. 6: Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.1 ml of 0.1 mol/L AA solution in DMSO were added to 4.8 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs, containing [Ag.sup.0]=210.sup.3 mol/L. Distribution of silver NPs by SDS and colloid absorption spectrum are demonstrated by curves 2 on FIG. 3a and FIG. 3b, respectively.

[0054] Example No. 7: Two separate solutions were prepared first as described below. 0.15 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.1 ml of 0.1 mol/L AA solution in DMSO were added to 4.8 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs, containing [Ag.sup.0]=210.sup.3 mol/L. Distribution of silver NPs by SDS and colloid absorption spectrum are demonstrated by curves 3 on FIG. 3a and FIG. 3b, respectively.

[0055] Example No. 8: Two separate solutions were prepared first as described below. 0.2 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.1 ml of 0.1 mol/L AA solution in DMSO were added to 4.7 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs, containing [Ag.sup.0]=210.sup.3 mol/L. Distribution of silver NPs by SDS and colloid absorption spectrum are demonstrated by curves 4 on FIG. 3a and FIG. 3b, respectively.

[0056] Conclusion: As shown in FIG. 3 and based on findings of the examples described above, stable colloidal solutions of silver NPs with the smallest SDS are produced when 0.01 mol/L tetraethylammonium hydroxide is used.

[0057] In the third panel of syntheses, the optimal concentration of reducing agent, ascorbic acid (AA), was selected to produce silver NPs, having maximum stability and minimum SDS.

[0058] Example No. 9: Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.05 ml of 0.1 mol/L AA solution in DMSO were added to 4.8 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs, containing [Ag.sup.0]=210.sup.3 mol/L. Distribution of silver NPs by SDS and colloid absorption spectrum are demonstrated by curves 1 on FIG. 4a and FIG. 4b, respectively.

[0059] Example No. 10: Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.1 ml of 0.1 mol/L AA solution in DMSO were added to 4.8 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs containing [Ag.sup.0]=210.sup.3 mol/L. Distribution of silver NPs by SDS and colloid absorption spectrum are demonstrated by curves 2 on FIG. 4a and FIG. 4b, respectively.

[0060] Example No. 11: Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.3 ml of 0.1 mol/L AA solution in DMSO were added to 4.6 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs, containing [Ag.sup.0]=210.sup.3 mol/L. Distribution of silver NPs by SDS and colloid absorption spectrum are demonstrated by curves 3 on FIG. 4a and FIG. 4b, respectively.

[0061] Example No. 12: Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.5 ml of 0.1 mol/L AA solution in DMSO were added to 4.4 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs containing [Ag.sup.0]=210.sup.3 mol/L. Distribution of silver NPs by SDS and colloid absorption spectrum are demonstrated by curves 3 on FIG. 4a and FIG. 4b, respectively.

[0062] Conclusion: As shown in FIG. 4 and based on findings of the examples described above, stable colloidal solutions of silver NPs with the smallest SDS are produced when 110.sup.3 mol/L ascorbic acid is used.

[0063] The fourth panel of examples studied the impact of the temperature of post-synthesis treatment and synthesis temperature on SDS and spectral characteristics of silver NPs.

[0064] Example No. 13: Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.1 ml of 0.1 mol/L AA solution in DMSO were added to 4.4 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. Synthesis was carried out at 25 C. This forms a solution of silver NPs, containing [Ag.sup.0]=210.sup.3 mol/L.

[0065] The solution was further heated at 50 C. for 100 min. Distribution of silver NPs by SDS and colloid absorption spectra during the heating process are demonstrated on FIG. 5a and FIG. 5b, respectively. Similar heating was carried out at 70 C. and 90 C. Colloid absorption spectra during the heating process are demonstrated on FIGS. 5c and 5d, respectively.

[0066] Conclusion: As shown in FIG. 5 and based on findings of the examples described above, silver NPs obtained in DMSO at 25 C. practically do not change their average SDS during post-synthesis treatment at 50 C.; spectral data, however, show the progress of the structuring process and crystallization of particles over time, therefore it is further recommended to heat particles for 100 minutes at 50 C. following synthesis. Heating above 50-70 C. results in aggregation of particles and partial coagulation of colloids.

[0067] Example No. 14: Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.1 ml of 0.1 mol/L AA solution in DMSO were added to 4.4 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. Synthesis was carried out at 25 C. This forms a solution of silver NPs containing [Ag.sup.0]=210.sup.3 mol/L. The solution was held at a room temperature for a month. FIG. 6 show changes in absorption spectra over time.

[0068] Conclusion: As shown in FIG. 6 and based on findings of the examples demonstrated above, silver NPs, obtained in DMSO at 25 C. practically do not change their characteristics and retain stable aggregation when held at 25 C. for 1 month.

[0069] Example No. 15: Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.1 ml of 0.1 mol/L AA solution in DMSO were added to 4.4 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. Synthesis was carried out at 25 C., 40 C., 60 C., 70 C. and 90 C. This forms a solution of silver NPs, containing [Ag.sup.0]=210.sup.3 mol/L. FIG. 7 demonstrate absorption spectra of colloids obtained.

[0070] Conclusion: As shown in FIG. 7 and based on findings of the examples described above, silver NPs, obtained in DMSO at above 25 C. form aggregates, as evidenced by increasing light absorbance at 500-600 nm. Therefore, synthesis should be carried out at a temperature below 25 C.

[0071] A further panel of experiments was intended to identify opportunities of obtaining silver NPs in DMSO using other biocompatible reducing agents, alternatives to ascorbic acid, in particular, such as glycerine, glucose, hydrogen peroxide and ethanol. Alternative biocompatible reducing agents may be used to relieve short-term pain syndrome associated with the presence of oxalate anion, a product of ascorbic acid oxidation, following intramuscular or intravenous administration of such medicinal product.

[0072] A further panel of experiments confirmed the possibility of using glycerine as a reducing agent in the method disclosed herein to produce a biocompatible colloidal solution of silver nanoparticles in a non-aqueous polar solvent.

[0073] Example No. 16: Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.5 ml of 10% glycerine solution were added to 4.4 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs, containing [Ag.sup.0]=210.sup.3 mol/L. Colloid absorption spectrum is demonstrated by curve 1 on FIG. 8.

[0074] The next panel of experiments confirmed the possibility to use glucose as a reducing agent in the method disclosed herein.

[0075] Example No. 17: Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.1 ml of 10% glucose solution were added to 4.8 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs, containing [Ag.sup.0]=210.sup.3 mol/L. Colloid absorption spectrum is demonstrated by curve 2 on FIG. 8.

[0076] The next panel of experiments confirmed the possibility to use ethyl alcohol as a reducing agent in the method disclosed herein.

[0077] Example No. 18: Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.2 ml of 10% ethyl alcohol solution were added to 4.7 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs, containing [Ag.sup.0]=210.sup.3 mol/L. Colloid absorption spectrum is demonstrated by curve 3 on FIG. 8.

[0078] The next panel of experiments confirmed the possibility to use hydrogen peroxide, having various concentrations as a reducing agent in the method disclosed herein.

[0079] Example No. 19: Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.05 ml of 10% H.sub.2O.sub.2 solution were added to 4.8 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs, containing [Ag.sup.0]=210.sup.3 mol/L. Colloid absorption spectrum is demonstrated by curve 4 on FIG. 8.

[0080] Example No. 20: Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.5 ml of 10% H.sub.2O.sub.2 solution were added to 4.4 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs containing [Ag.sup.0]=210.sup.3 mol/L. Colloid absorption spectrum is demonstrated by curve 5 on FIG. 8.

[0081] Example No. 21: Two separate solutions were prepared first as described below. 0.1 ml of 1.0 mol/L aqueous tetraethylammonium hydroxide (Et.sub.4NOH) solution and 0.75 ml of 10% H.sub.2O.sub.2 solution were added to 4.1 mL of DMSO. Then, 5.0 ml of 0.004 mol/L AgNO.sub.3 solution in DMSO was added to this solution under vigorous stirring. This forms a solution of silver NPs, containing [Ag.sup.0]=210.sup.3 mol/L. Colloid absorption spectrum is demonstrated by curve 6 on FIG. 8. Electron microphotographs of colloid silver NPs are shown on FIG. 9.

[0082] Therefore, the invention disclosed herein allows obtaining a biocompatible colloidal solution of silver nanoparticles in a non-aqueous polar solvent in a form suitable for introduction of silver nanoparticles into soft dosage forms and cosmetic productsointments and creams, and obtaining a biocompatible colloidal solution of silver nanoparticles in a non-aqueous polar solvent, the use of which avoids pain associated with administration of the product.