CN116648138A

CN116648138A - Lactam composition and use

Info

Publication number: CN116648138A
Application number: CN202180081479.4A
Authority: CN
Inventors: N·J·布朗比尔; J·C·奥基夫; N·J·帕里
Original assignee: Unilever IP Holdings BV
Current assignee: Unilever IP Holdings BV
Priority date: 2020-12-09
Filing date: 2021-11-05
Publication date: 2023-08-25
Also published as: WO2022122265A1; EP4258868A1

Abstract

The present invention relates to a composition comprising: (a) 0.0001-5 wt% of a lactam; and (b) 1-80 wt% solvent; wherein the composition has a pH of 4 to 6.50; wherein the lactam is selected from the following formulas. The invention also relates to a method of treating a surface to improve the resistance of the surface to bacterial fouling; and also to the use of a combination of a solvent in a lactam composition and a pH of 4 to 6.50 applied to the composition to improve the solubility and stability of the lactam in the composition.

Description

Lactam composition and use

Technical Field

The present invention relates to improvements in the hygiene field, in particular to compositions comprising lactams, which exhibit improved lactam solubility and stability.

Background

Sanitation, particularly inhibition of bacterial species, is important to consumers.

Lactams are known as inhibitors of bacterial species. They may be applied to surfaces to inhibit bacterial species.

It is desirable to improve the usability of lactams and to provide formulations that exhibit improved lactam solubility and stability.

Disclosure of Invention

We have found that by formulating a composition comprising a lactam in combination with a solvent at a pH of 4-6.50, the resulting formulation exhibits improved solubility and stability of the lactam.

In a first aspect, the present invention relates to a composition comprising: -

(a) 0.0001 to 5 wt%, preferably 0.0001 to 2.5 wt%, more preferably 0.0001 to 1 wt%, and even more preferably 0.001 to 1 wt% of a lactam; and

(b) 0.5 to 95 wt%, preferably 0.5 to 90 wt%, more preferably 0.5 to 80 wt% of a solvent;

wherein the composition has a pH of 4 to 6.50, preferably a pH of 4 to 6.25, more preferably a pH of 4.50 to 6.00;

wherein the lactam is selected from the group consisting of:

and +.>

Preferably the pH is 4-5.40, more preferably 4.50-5.40.

More preferably, the lactam is selected from:

and/or +.>

Most preferably, the lactam is:

(4-chlorophenyl) -5-methylene-pyrrol-2-one.

Preferably, the lactam is delivered from a water-based composition, preferably it comprises 0.1 to 98 wt%, preferably 0.5 to 80 wt%, more preferably 1 to 75 wt% water.

The solvent is selected from: an alcohol; levulinate derivatives; lactic acid ester derivatives; and a solvent having a dielectric constant of 15 or more, preferably the solvent is selected from the group consisting of: alcohols, levulinate derivatives; and lactate derivatives; more preferably the solvent is selected from: levulinate derivatives and lactate derivatives.

Preferred examples of solvents are: alcohols, preferably C1-C4 alcohols, more preferably ethanol; lactate derivatives, preferably ethyl lactate and/or butyl lactate; levulinate derivatives, preferably 2-methyltetrahydrofuran, ethyl levulinate and/or ethyl Levulinate Glycerol Ketal (LGK); and a solvent having a dielectric constant of 15 or more, preferably Dimethylsulfoxide (DMSO).

Preferably, the solvent is selected from: ethanol; ethyl lactate, butyl lactate; 2-methyltetrahydrofuran, ethyl levulinate, and ethyl Levulinate Glycerol Ketal (LGK), or mixtures thereof.

Preferably, the solvent is selected from: levulinate derivatives; and lactate derivatives.

Most preferably, the solvent is selected from: ethyl lactate, butyl lactate; 2-methyltetrahydrofuran, ethyl levulinate, and ethyl Levulinate Glycerol Ketal (LGK), or mixtures thereof.

The solvent is present at a level of 0.5 to 95 wt%, preferably 0.5 to 90 wt%, more preferably 0.5 to 80 wt%. The solvent may be present at a minimum level of 0.5 wt%, 0.75 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, or even 5 wt%. The solvent may be present at a highest level of 95 wt%, 90 wt%, 85 wt%, 80 wt%, 70 wt%, 60 wt%, 50 wt%, 40 wt%, 30 wt%, 25 wt%, 20 wt%, or even 10 wt%. Any higher level of solvent is intended to be combinable with any lower level of solvent.

Preferably, the composition comprises one or more surfactants. The surfactant may be present at a level of from 0.25 to 25 wt%, preferably from 0.25 to 20 wt%, more preferably from 0.25 to 15 wt%, even more preferably from 0.25 to 10 wt%, or even from 0.5 to 10 wt% or even from 0.5 to 5 wt%.

The surfactant may be present at a level of from 0.25 to 25 wt%, preferably from 0.25 to 20 wt%, more preferably from 0.25 to 15 wt%, even more preferably from 0.25 to 10 wt%, or even from 0.5 to 10 wt% or even from 0.5 to 5 wt%.

The surfactant is preferably selected from anionic, nonionic, cationic and/or amphoteric surfactants. Preferred surfactants are nonionic surfactants.

The composition preferably comprises a buffer.

In a second aspect, the present invention relates to a method of treating a surface by treatment with a composition according to the first aspect of the invention to improve the resistance of the surface to bacterial contamination.

Preferably, the surface to be treated is selected from plastics, metals, wood, polymers, paper, fabrics and/or wipes.

Preferably, in the method, the lactam is selected from:

and/or +.>Preferably +.>

In a third aspect, the invention also relates to the use of a combination of a solvent in a lactam composition and a pH of 4-6.5, preferably 4-6.25, more preferably 4.50-6.00 applied to the composition for improving the solubility and stability of the lactam in the composition.

Preferably, in said use, the lactam is selected from:

and/or +.>Preferably +.>

Drawings

Fig. 1 is a photograph showing the solubility of lactam 488 at pH 5, pH 7 and pH 8.

Figure 2 shows the effect of pH on the solubility and stability of lactam 488. The initial solubility (left hand axis and rounded data points) and stability (right hand axis and square data points) of the lactam was delivered in ethanol to a total of 2% solvent and 100ppm lactam in solution vs buffer pH.

Detailed Description

The indefinite articles "a" or "an" and their corresponding definite articles "the" as used herein mean at least one, or one or more, unless otherwise specified.

It should be understood that all preferences are combinable unless explicitly stated otherwise.

Lactam

The lactam is a cyclic amide. The lactam is a lactam selected from the group consisting of:

more preferably, the lactam is selected from:

and/or +.>

Most preferably, the lactam is:

(4-chlorophenyl) -5-methylene-pyrrol-2-one.

When the lactam is cationic in nature, it may be used either as a cation or with a suitable counter ion (e.g. iodide).

Lactam level

Preferably the lactam is present at a level of 0.0001 to 2.5 wt%, preferably 0.0001 to 1 wt%. For example, the lactam may suitably be present at a level of 0.001 to 1 wt%, or even 0.01 to 0.5 wt%.

Composition and method for producing the same

Preferably, the lactam is delivered from a water-based composition, preferably it comprises 0.1 to 98 wt%, preferably 0.5 to 80 wt%, more preferably 1 to 75 wt% water. The composition may comprise any amount of water ranging from a lower amount of 0.1, 0.5, 1, 1.5, 2 or even 5 wt% water up to 30, 40, 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98 or even 99 wt% water.

Solvent(s)

The composition comprises a solvent.

Preferred solvents are selected from: an alcohol; levulinate derivatives; lactic acid ester derivatives; and a solvent having a dielectric constant of 15 or more. Preferred examples of solvents are: alcohols, preferably C1-C4 alcohols, more preferably ethanol; lactate derivatives, preferably ethyl lactate and/or butyl lactate; levulinate derivatives, preferably 2-methyltetrahydrofuran, ethyl levulinate and/or ethyl Levulinate Glycerol Ketal (LGK); and a solvent having a dielectric constant of 15 or more, preferably Dimethylsulfoxide (DMSO).

Preferably, the solvent is selected from: ethanol; ethyl lactate, butyl lactate; 2-methyltetrahydrofuran (2 Me-THF), ethyl levulinate and ethyl Levulinate Glycerol Ketal (LGK), or mixtures thereof.

2Me-THF, ethyl levulinate, and LGK can be categorized as levulinate derivatives (or levulinate derivatives). Levulinic acid can be derived from lignocellulosic biomass (i.e., corn hulls, bagasse, etc.), and can be converted to 2Me-THF in a cyclization reaction, ethyl levulinate in a one-step esterification, and LGK in two steps (esterification and ketal synthesis).

Ethyl lactate and butyl lactate are lactic acid (lactate) derivatives. Lactic acid is a byproduct of fermentation, which is then reacted with ethanol or butanol to produce ethyl lactate and butyl lactate.

The solvent may be present at a level of from 1 to 80 wt%, preferably from 1 to 50 wt%, more preferably from 1 to 40 wt%. The solvent level may also be 1 to 30 wt%, 1 to 20 wt%, or even 1 to 15 wt% or 1 to 10 wt%.

The composition may preferably comprise a buffer to help maintain any resulting composition within a specified pH range. The buffer system may be any conventional buffer system known in the art. These may include, for example, citrate, acetate, phosphate and/or carbonate buffers, or mixtures thereof.

Further ingredients

The composition may comprise further ingredients such as surfactants, chelating agents, thickeners, pH modifiers and perfumes.

The invention will be further described by the following non-limiting examples.

Examples

Example 1 preparation of preferred lactam examples

Preparation of 4- (4-chlorophenyl) -5-hydroxy-5-methylfuran-2 (5H) -one

1- (4-chlorophenyl) propan-2-one (40.00 g,34.75mL,237.2 mmol), glyoxylate monohydrate (32.75 g,355.8 mmol) and phosphoric acid (69.74 g,711.7 mmol) were combined at room temperature and then heated to 85℃overnight. After cooling to room temperature, the mixture was poured into a mixture of water (500 mL) and ethyl acetate (500 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (500 mL). The combined organic layers were washed with a 1:1 mixture of water and brine (2×500 mL), dried (MgSO ₄ ) And concentrated under reduced pressure to give 4- (4-chlorophenyl) -5-hydroxy-5-methylfuran-2 (5H) -one (66.00 g,>100% yield) as brown oilA shape. This material was used in the next step without further purification.

Preparation of 4- (4-chlorophenyl) -5-hydroxy-5-methyl-1H-pyrrol-2 (5H) -one

4- (4-chlorophenyl) -5-hydroxy-5-methylfuran-2 (5H) -one (66.00 g,293.8 mmol) was dissolved in thionyl chloride (196.8 g,120.0mL,1654 mmol) and heated at 40℃for 1 hour, then at 80℃for 2 hours. The mixture was concentrated under reduced pressure and azeotroped with 2-methyltetrahydrofuran (200 mL). The residue was diluted with 2-methyltetrahydrofuran (160 mL) and the solution was added to a cooled stirred mixture of 28% aqueous ammonia (180 mL) in 2-methyltetrahydrofuran (20 mL) at 0 ℃. The mixture was warmed to room temperature and stirred overnight. Water (100 mL) and ethyl acetate (200 mL) were added and the layers separated. The aqueous phase was extracted with ethyl acetate (200 mL) and the combined organic extracts were dried (MgSO ₄ ) And concentrated under reduced pressure. Purification by dry flash column chromatography (5-60% ethyl acetate in heptane) afforded 4- (4-chlorophenyl) -5-hydroxy-5-methyl-1H-pyrrol-2 (5H) -one (23.18 g,35% yield) as a cream solid.

¹ H NMR(400MHz,d ₆ -DMSO)8.55(brs,1H),7.88-7.83(m,2H),7.51-7.46(m,2H),6.37(d,1H),6.32(s,1H),1.45(s,3H)

UPLC (alkaline) 1.51/5.00min,100% purity, M+H ⁺ 224

MP 177℃

Preparation of 4- (4-chlorophenyl) -5-methylene-1H-pyrrol-2 (5H) -one

To a cooled solution of 4- (4-chlorophenyl) -5-hydroxy-5-methyl-1H-pyrrol-2 (5H) -one (10.00 g,44.51 mmol) in anhydrous dichloromethane (100 mL) at 0deg.C for 15 min was added boron trifluoride etherate (8.213 g,7.142 mL)57.87 mmol) in anhydrous dichloromethane (45 mL). The mixture was stirred at 0 ℃ and then slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched with ice water (100 mL) and the layers separated. The aqueous layer was extracted with dichloromethane (100 mL) and the combined organic layers were washed with a 1:1 mixture of water and saturated aqueous sodium bicarbonate (100 mL), dried (MgSO ₄ ) And filtered. Silica was added to the filtrate and the mixture was stirred for 10 minutes, then filtered through a plug of silica, washed thoroughly with dichloromethane, then with a 3:1 mixture of dichloromethane and diethyl ether. . Fractions containing the desired product were combined and concentrated under reduced pressure. A precipitate formed upon concentration, which was collected by filtration, and washed with diethyl ether to give 4- (4-chlorophenyl) -5-methylene-1H-pyrrol-2 (5H) -one (5.25 g,57% yield) as a cream solid.

¹ H NMR(400MHz,d ₆ -DMSO)10.10(s,1H),7.54-7.47(m,4H),6.36(s,1H),5.04(t,1H),4.85(s,1H)

UPLC (alkaline) 1.87/5.00min,100% purity, M+H ⁺ 206

MP 182℃

Preparation of 5-hydroxy-5-methyl-4- (p-tolyl) furan-2 (5H) -one

1- (p-tolyl) propan-2-one (25.00 g,24.00mL,168.7 mmol), glyoxylate monohydrate (23.29 g,253.0 mmol) and phosphoric acid (49.60 g,506.1 mmol) were combined at room temperature and then heated overnight at 90 ℃. After cooling to room temperature, the mixture was poured into a stirred mixture of ice water (400 mL) and ethyl acetate (400 mL). The layers were separated and the organic phase was washed with water (100 mL), dried (MgSO ₄ ) And concentrated under reduced pressure. The mixture was azeotroped with 2-methyltetrahydrofuran (50 mL) to give 5-hydroxy-5-methyl-4- (p-tolyl) furan-2 (5H) -one (16.50 g,48% yield) as a brown solid.

¹ H NMR(400MHz,d ₆ -DMSO)7.86(s,1H),7.75(d,2H),7.28(d,2H),6.59(s,1H),2.32(s,3H),1.61(s,3H)

Preparation of 5-hydroxy-5-methyl-4- (p-tolyl) -1H-pyrrol-2 (5H) -one

5-hydroxy-5-methyl-4- (p-tolyl) furan-2 (5H) -one (16.50 g,80.80 mmol) was dissolved in thionyl chloride (48.06 g,29.47mL,404.0 mmol) and heated at 50℃for 1 hour, then at reflux for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure and azeotroped with 2-methyltetrahydrofuran (2×50 mL). The residue was diluted with 2-methyltetrahydrofuran (60 mL) and the solution was added at 0deg.C to a cooled stirred mixture of 28% aqueous ammonia (55 mL,808.0 mol) in 2-methyltetrahydrofuran (10 mL). The mixture was warmed to room temperature and stirred overnight. The 2-methyltetrahydrofuran was removed under reduced pressure, the residue was diluted with water (200 mL) and diethyl ether (100 mL), and the mixture was stirred at room temperature for 20 min. The solid was collected by filtration and stirred at room temperature in water (100 mL) and diethyl ether (50 mL) for 10 min. The solid was collected by filtration, washed with water, diethyl ether, and dried under vacuum at 50 ℃ to give 5-hydroxy-5-methyl-4- (p-tolyl) -1H-pyrrol-2 (5H) -one (10.49 g,31% yield) as a pale beige solid.

¹ H NMR(400MHz,d ₆ -DMSO)8.44(brs,1H),7.73(d,2H),7.21(d,2H),6.24(s,2H),2.29(s,3H),1.45(s,3H)

¹³ C NMR(400MHz,d ₆ -DMSO)170.4(s,1C),161.1(s,1C),139.8(s,1C),129.7(s,2C),128.9(s,1C),128.2(s,2C),119.1(s,1C),87.8(s,1C),26.7(s,1C),21.5(s,1C)

UPLC (alkaline) 1.41/5.00min,100% purity, M+H ⁺ 204

MP 178 ℃ decomposition

Preparation of 5-methylene-4- (p-tolyl) -1H-pyrrol-2 (5H) -one

To a cooled solution of 5-hydroxy-5-methyl-4- (p-tolyl) -1H-pyrrol-2 (5H) -one (8.68 g,42.7 mmol) in anhydrous dichloromethane (87 mL) was added a solution of boron trifluoride etherate (6.85 g,5.96mL,55.5 mmol) in anhydrous dichloromethane (40 mL) at 0deg.C over 15 min. After 1 hour, the mixture was allowed to slowly warm to room temperature. After a further 3 hours, the reaction was diluted with dichloromethane (50 mL) and ice water (100 mL) and stirred for 10 minutes. The layers were separated and the organic layer was washed with water (100 mL), a 1:1 mixture of water and saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL) and the organic layer was filtered through celite, washing with dichloromethane. Any excess water was removed by pipette and the filtrate was dried (MgSO ₄ ) And concentrated under reduced pressure to a brown solid. The solid was stirred in hot dichloromethane (120 mL) for 15 min, then slowly cooled to room temperature, and then cooled to 0 ℃. The solid was collected by filtration to give 5-methylene-4- (p-tolyl) -1H-pyrrol-2 (5H) -one (3.87 g,49% yield) as a yellow solid. Silica was added to the filtrate and the mixture was stirred for 10 minutes, then filtered through a plug of silica, washed thoroughly with dichloromethane, then with a 4:1 mixture of dichloromethane and diethyl ether. The filtrate was concentrated under reduced pressure to give 5-methylene-4- (p-tolyl) -1H-pyrrol-2 (5H) -one (0.58 g, 7%) as a yellow solid. Total yield of 5-methylene-4- (p-tolyl) -1H-pyrrol-2 (5H) -one (4.45 g,56% yield).

¹ H NMR(400MHz,d ₆ -DMSO)10.11(brs,1H),7.35(d,2H),7.25(d,2H),6.25(s,1H),5.01(s,1H),4.85(s,1H),2.31(s,3H)

UPLC (alkaline) 1.83/5.00min,100% purity, M+H ⁺ 186

MP 200 ℃ decomposition

The materials used

In the examples below, lactam 488 is used.

This is 4- (4-chlorophenyl) -5-methylene-pyrrol-2-one and the structure is shown below: -

Example 2

This example shows the effect of pH on the solubility of a lactam in a water-based composition comprising a solvent. A stock solution of lactam 488 at a target 10000ppm in ethanol was prepared and placed on a bottle roller (bottle roller) for 24 hours, then filtered through a syringe filter to produce a saturated solution (possibly about 8000ppm in ethanol). The stock solution was mixed with 0.1M acetate buffer at pH 5.2 or with 0.1M phosphate buffer at pH 7 or 8 in a ratio of 1:2, stirred in a vial and any precipitate formed was observed visually, indicating insolubility. From fig. 1 (glass picture) it can be seen that the lactam is mostly dissolved to an acceptable level at pH 5, whereas the solubility is greatly reduced at pH 7 and 8.

Example 3

This example demonstrates the lack of stability of the lactam composition at a pH below pH 4 and above pH 6.5.

Initial lactam solubility (3 hours) was measured by preparing a 5mg/ml solution of lactam 488 in ethanol. A 0.1M phosphate/citrate/carbonate mixed buffer was prepared and adjusted to a pH range of 2-10 (precise values in fig. 2 and table 1), then lactam 488/EtOH stock solution was added to a total of 2%, corresponding to the theoretical 100ppm lactam concentration in solution.

The solution was equilibrated for 3 hours, and then 200 μl of 7 replicates each was dispensed into a 96-well microtiter plate (Greiner, UV-Star), with well 8 as a background free of lactam. UV absorbance spectra were recorded in the range of 200-450nm on a Varioskan Lux UV/Vis plate reader to quantify the intensity of the lactam peak (lambda _max =280 nm) and the signal was converted to ppm lactam in solution for calibration of the known EtOH/lactam solution.

Using a solution state ¹ H NMR measured long term lactam stability. Lactam 488 was dissolved to a maximum concentration (10 mg/mL) in d6-DMSO and combined at a ratio of 2:1 with a series of pH buffers (pH 7.4.0.2M phosphate buffer, pH 6.1M citrate buffer, pH 5.2.0.1M acetate buffer)4, 2) and water. These samples were then filtered and inhibited by water ¹ H NMR was studied at weekly time points for 4 weeks. The integration of the buffer peak was used to quantify the relative% of residual lactam compared to the lactam resonance at 5.22 ppm.

Results of lactam stability and solubility are shown in FIG. 2 for UV/Vis and ¹ h NMR data showed. The values in fig. 2 are also shown in table 1.

pH buffer	Lactam concentration (3 hours) (ppm)	% residual lactam (4 weeks)
			2	>80*	20
3.12	80.53	～30*
			4.08	77.83	50
5.22	73.53	80
			6.21	72.22	60
7.08	67.90	20
			8.05	67.68	<10*
8.92	68.43	5
			9.84	63.17	<5*

Table 1 initial concentrations calculated using UV/Vis spectroscopy, attenuation measured by NMR spectroscopy-values with x were not measured, but estimated by extrapolation from the plot

For compositions in which the pH is 4-6.5, the lactam only initially dissolves and exhibits long-term stability (4 weeks). Above this pH, the composition is not sufficiently soluble and is also unstable, while below pH 4, the composition is unstable.

Claims

1. A composition comprising:

(b) 1 to 80 wt%, preferably 1 to 50 wt%, more preferably 1 to 40 wt% of a solvent;

wherein the composition has a pH of from 4 to 6.50, preferably from 4 to 6.25, more preferably from 4.50 to 6.00;

wherein the lactam is selected from the group consisting of:

and +.>

2. The composition according to claim 1, wherein the pH is 4-5.40, preferably 4.50-5.40.

3. The composition of claim 1 or claim 2, wherein the lactam is selected from the group consisting of:

and/or +.>

4. The composition of any one of the preceding claims, wherein the lactam is:

4- (4-chlorophenyl) -5-methylene-pyrrol-2-one.

5. The composition according to any of the preceding claims, wherein the composition is a water-based composition, preferably comprising 0.1 to 98 wt%, preferably 0.5 to 80 wt%, more preferably 1 to 75 wt% water.

6. The composition of any of the preceding claims, wherein the solvent is selected from the group consisting of: an alcohol; levulinate derivatives; lactic acid ester derivatives; and a solvent having a dielectric constant of 15 or more; preferably the solvent is: alcohols, preferably C1-C4 alcohols, more preferably ethanol; lactate derivatives, preferably ethyl lactate and/or butyl lactate; levulinate derivatives, preferably 2-methyltetrahydrofuran, ethyl levulinate and/or ethyl Levulinate Glycerol Ketal (LGK); and a solvent having a dielectric constant of 15 or more, preferably Dimethylsulfoxide (DMSO).

7. The composition of any of the preceding claims, wherein the solvent is selected from the group consisting of: ethanol; ethyl lactate, butyl lactate; 2-methyltetrahydrofuran, ethyl levulinate, and ethyl Levulinate Glycerol Ketal (LGK), or mixtures thereof; ethyl lactate and butyl lactate are preferred; 2-methyltetrahydrofuran, ethyl levulinate, and ethyl Levulinate Glycerol Ketal (LGK), or mixtures thereof.

8. The composition of any of the preceding claims, wherein the solvent is selected from the group consisting of: ethyl lactate, butyl lactate; 2-methyltetrahydrofuran, ethyl levulinate, and ethyl Levulinate Glycerol Ketal (LGK), or mixtures thereof.

9. The composition of any one of the preceding claims, wherein the composition comprises a buffer system.

10. A method of treating a surface by treatment with a composition according to any one of claims 1 to 9 to improve the resistance of the surface to bacterial fouling.

11. The method according to claim 10, wherein the surface to be treated is selected from plastic, metal, wood, polymer, paper, fabric and/or wipe.

12. The method of claim 10 or claim 11, wherein the lactam is selected from the group consisting of:

and/or +.>Preferably +.>

13. Use of a combination of a solvent in a lactam composition and a pH of 4-6.50 applied to the composition, preferably a pH of 4-6, more preferably a pH of 4.50-5.50, for improving the solubility and stability of the lactam in the composition.

14. The use according to claim 14, wherein the lactam is selected from the group consisting of:

and/or +.>Preferably +.>