WO2000002844A1

WO2000002844A1 - Quaternary ammonium salts, polymeric film containing them and colorimetric device

Info

Publication number: WO2000002844A1
Application number: PCT/GB1999/002081
Authority: WO
Inventors: Jafar Albadran; Neil Hamilton Mcmurray
Original assignee: Sensormetrix International Limited
Priority date: 1998-07-11
Filing date: 1999-07-12
Publication date: 2000-01-20
Also published as: EP1097123A1; AU4790399A; GB9815001D0

Abstract

There is described a polymeric quaternary alkyl ammonium cation of general formula (I), or a salt thereof; in which R1, R2, R3 and R4, which may be the same or different are each alkyl C1 to 20; m is an integer from 1 to 100; and n is an integer from 1 to 7. There is also described a film formulation comprising a cation of formula (I), a colorimetric sensor device comprising said film and an endotracheal intubation apparatus comprising a sensor.

Description

QUATERNARY AMMONIUM SALTS, POLYMERIC FILM CONTAINING THEM AND COLORIMETRIC DEVICE

This invention relates to oligomeric/polymeric quaternary alkyl ammonium cations, and salts thereof, for incorporation in colorimetric film sensors particularly for the detection of carbon dioxide.

Carbon dioxide sensors are known which incorporate quaternary alkyl ammonium salts of pH indicator dye acids and carbonic acid within a thin transparent polymer membrane. They act as rapidly responding, reversible and non-consumpting detectors of carbon dioxide in the gas phase. Such sensors respond by changing colour on exposure to carbon dioxide. Furthermore, the response may be made quantitative by monitoring optical absorbance e.g. using monochromatic light. Colour change occurs through the reversible protonation of the indicator dye anion by carbonic acid formed by the reversible reaction of carbon dioxide with water bound within the film. Such sensor films have applications in medicine, horticulture, air conditioning systems, environmental monitoring and industrial health and safety.

The use of such quaternary alkyl ammonium salts is described in, inter alia, US Patent No. 5,005,572, European Patent No. EP 0 509 998 and International Patent Application No. WO 96/24054.

Known quaternary alkyl ammonium cations, and their salts, tend to be mobile within a sensor film and can therefore by lost through migration. Migration places significant restriction on the choice of sensor substrate (which must be compatible with the quaternary alkyl ammonium salt).

Also, known quaternary alkyl ammonium salts are not universally compatible with organic polymers, further restricting the choice of polymers for sensor film formulation. We have now surprisingly found that a high molecular weight oligomeric/polymeric quaternary alkyl ammonium cation, or salts thereof, which are less mobile within a sensor film reducing the extent to which migration can occur. Reduced migration allows a wider choice of substrate materials which may now be thermodynamically compatible with the quaternary ammonium salt.

According to the invention we provide a polymeric quaternary alkyl ammonium cations of the general formula I and salts thereof.

Ri R₃

I I

-(CH₂)_n-^[-(CB,)_n-N⁺-]_m- I I ^R2 ^R4

in which R,, R₂, R₃ and R₄, which may be the same or different, are each alkyl Cl to C20; m is an integer from 1 to 100; and n is an integer from 1 to 7.

By the term polymeric, it is also intended to include oligomeric.

Ri, R₂, R₃ and R₄, which may be the same or different, are preferably alkyl C5 to 10. It is preferred that the values of n and m together should have a total in the range of from 4 to 8.

Preferably, m is an integer from 1 to 50, more preferably from 1 to 25, especially 1 to 10 and particularly 1 to 7.

Particularly preferred salts are 1,8-octane-di-tripentyl ammonium bromide and 1,8- octane-di-tripentyl ammonium hydroxide. The salts of the cations of formula I may be selected from the group halide e.g. fluoride, chloride, bromide or iodide; hydroxide; carbonate and tetrafluoroborate. Of the halides, bromide salts are preferred, but especially preferred are the hydroxide salts.

These provide increased migration/leaching resistance for the quaternary alkyl ammonium pH mdicator dye salts and bicarbonate salts essential for sensor function.

The cations of formula I, and thereof, are advantageous in that they produce an improved pH indicator dye with a greater compatibility with polymers, therefore allowing a wider choice of polymers for sensor film formulation.

According to a further feature of the invention we provide a film formulation comprising a cation of formula I, or a salt thereof, in intimate mixture with a transparent film-forming polymer vehicle.

The transparent film-forming polymer vehicle should be compatible with the indicator material, such that the latter does not exude or otherwise undergo phase separation over a prolonged period (for the intended lifetime of the sensor). Thus, the film-forming polymer should be volatile, e.g. at room temperature and the polymeric quaternary ammonium cation, or a salt thereof, should be soluble in the polymer. The film-forming polymer vehicle should preferably be hydrolytically stable in order to avoid unwanted changes in the pH in the absence of carbon dioxide. The polymer should furthermore be permeable to carbon dioxide.

The hydrolytically stable film-forming polymer may be water-soluble or organic solvent-soluble. It is preferred that the film-forming polymer is organic solvent soluble. Examples of suitable organic solvent soluble film-forming polymers include polyvinyl butyral, polyvinyl methyl ether, polymethyl ether, polymethyl methacrylate, ethyl cellulose and polystyrene. Examples of water-soluble film-forming polymers which also have good resistance to hydrolysis include hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol (100% hydrolised) and polypropylene glycol.

Further examples of polymers include polydimethyl silicone, and polyurethane.

According to another feature of the invention we provide a colorimetric sensor device containing one or more of the aforementioned quaternary ammonium salts. Such a device may generally comprise;

a polymeric quaternary ammonium cation of formula I, or a salt thereof; at least one pH sensitive dye; and a film-forming polymer.

Any conventionally known pH sensitive dyes may be used, including thymol blue, m-cresol purple, xylenol blue and/or cresol-red.

The volatile polymer or oligomer may be any such material which is conventionally known in the art, for example, such as is described in PCT patent application No. WO96/24054 which describes that the film forming component is preferably a water- insoluble low volatility organic substance, which is not susceptible to alkaline hydrolysis and is liquid at temperatures below 100°C, e.g. at room temperature, or is semi-solid e.g. of waxy structure, at room temperature.

Compounds which are "susceptible to alkaline hydrolysis" includes compounds such as those containing ester groups which are subjected to alkaline hydrolysis in the presence of a basic component.

The film forming component may have a molecular weight (weight average molecular weight = M„,) below 15,000, preferably below 10,000. The film forming component may be selected from the group consisting of alcohols, phenols and alkoxylated derivatives of such substances, e.g. having at least one linear or branched polyether. The film forming component may have be a compound having one of the following structures:

R⁹-(O-R¹⁰)_χ-(O-R^π)_y-O-R¹² (I)

R⁹-(CH₂-(O-R¹⁰)_x-(O-Rⁿ)_y-O-R^I2)_p (II)

R⁹-S-R¹³-(O-R¹⁰)_x-(o-Rⁿ)_y-O-R¹² (HI)

(R⁹) -N(R¹³-(O-R^,0)_x-(O-R^u)_y-O-R¹²)_r (IV)

wherein R⁹ and R¹² each represents H or a linear or branched hydrocarbon residue of 1 to 50 carbon atoms, optionally containing one or more double bonds, triple bonds and/or ring structures,

R¹⁰, R¹¹ and R¹³ each represents a linear or branched hydrocarbon residue of 1 to 10 carbon atoms, x and y are equal or different integers from 0 to 100, p is an integer from 1 to 6, and q and r are equal or different integers from 0 to 4.

Examples of compounds having the above structures (I) to (IV) are the following:

Polyalkylene glycols, such as polyethylene glycols, polyethylene glycols, polypropylene glycols, polybutylene glycols and copolymers of ethylene oxide, propylene oxide and/or butylene oxide. Other linear polyethers, such as polytetrahydrofurans. Alkoxylated alcohols or phenols, such as ethoxylated, propoxylated or butoxylated alcohols derived from fatty alcohols (straight or branched, saturated or unsaturated, etc), alkyl phenols, dialkyl phenols, alkyl naphthalenes, bisphenol A, alkyne diols, lanolin, cholesterol, phytosterol, sitosterol, glucose ethers and silicones; and mixed ethoxylated/propoxylated alcohols. Branched polyethers, for instance products obtained by ethoxylating and/or propoxylating trimethylol propane or pentaerythritol. Alkoxylated amines, such as ethoxylated and/or propoxylated primary or secondary amines or diamines. Alkoxylated (ethoxylated and/or propoxylated) thiols. Dialkyl ethers, e.g. dioctyl ether.

Silicone oligomers or polymers may also be used since they have the advantage that, inter alia, they are highly permeable to carbon dioxide. For example, a typical silicone polymer has permeability (that is, the gas transmission rate of a film of the polymer of thickness 0.001 inch, expressed as cubic centimetres of gas transmitted through 1 mm of film per 24 hours per square inch of film with one atmosphere differential across the film) is typically as follows:

About 100,000 for oxygen and about 500,000 for carbon dioxide (compared with figures of respectively about 1,000 and 5,000 for PTFE; 500 and 2,000 for low density polyethylene; 100 and 500 for cellulose acetate; and 1 and 1 for poly vinylidene chloride) .

The silicone oligomers and polymers are, easy to handle and to apply to a suitable substrate using an organic solvent such as a hydrocarbon type solvent (such as hexane), a chlorinated solvent (for example, chloroform or dichloromethane), an ether solvent (such as tetrahydrofuran), or a low molecular weight oligomeric silicone (such as a cyclic dimethyl silicone).

Because the silicone oligomers or polymers are substantially non-curable they have good storage stability and can be stored indefinitely in the solvent.

The silicone oligomers or polymers are also readily compatible with the pH sensitive dye and the basic substance, and can be applied in the form of a film on a preformed substrate (such as a plastics, paper or glass substrate). Alternatively, the silicone may be applied as an impregnation throughout a porous carrier medium, for example, of glass fibre, paper, plastics, textile fabric or the like. It is particularly preferred to use such materials which have been provided with a hydrophobic surface treatment, for example, by silanisation.

The silicone oligomers or polymers are preferably substantially linear and substantially free of hydrophilic groups; preferred substituents for the silicone chain are methyl groups (although other low molecular weight hydrophobic groups may be employed, such as ethyl or trifluoromethyl groups).

It is particularly preferred that the silicone oligomer or polymer is a linear polydimethylsiloxane. The silicone preferably has a molecular weight in the range of 200 to 200000, and is preferably optically transparent. When higher molecular weight silicone polymers are used they are very good binders and have a low glass transition temperature such that they maintain their physical properties over a wide range of temperatures. They are furthermore non-toxic and non- volatile, and hydrolytically stable.

The silicone oligomers or polymers are furthermore compatible with the indicator ingredients (the dye and the basic substrate), and can be free of migratable low molecular weight materials such as plasticisers or the like. .

Preferably the device will be in the form of film sensor and the film may therefore require a support such as a polypropylene proper sheet, a cellulose layer or a plastics foil material. However, the sensor of the invention preferably comprises a silanised paper support which is preferably non-translucent i.e. is reflective, such as a white film which aids in visual indication. Alternatively the support may be a transparent film on a glass substrate which permits quantitative interrogation with e.g. monochromatic light.

The sensor device of the invention functions by the reaction of carbon dioxide with traces of water bound within the sensor film to form carbonic acid (H₂CO₃). Thus, dissociation of H₂CO₃ to H⁺ and HCO₃ ^' produces a fall in sensor pH which in turn produces an optical absorbance change through the reversible protonation of the pH indicator dye.

Thus, according to a further feature of the invention we provide a method of carbon dioxide detection which comprises placing a sensor accordmg to the invention in situ and observing a colour change.

The sensors of the invention have particular utility in determining the proper placement of a tracheal tube of an endotracheal intubation device in a patient.

Thus, a further feature of the invention is to provide an endotracheal apparatus comprising a sensor as hereinbefore described.

We further provide a method for determining the proper placement of an endotracheal tube which comprises inserting an endotracheal tube comprising a sensor according to the invention, into a patient and observing a colour change.

The invention will now be described, but in no way limited by the following examples.

Example 1

Preparation of 1,8 Octane-di-tripentyl Ammonium Bromide

Chemicals

• Tri Pentyl Amine (TPA) 97%, fw: 227.44, bP: 81-83°C, d: 0.788.

• 1,8-Dibromooctane (DBO) 98%, fw: 286.06, bp: 270-272°C, d: 1.477. • Methanol, d: 0.791. Experimental and Results

The reactants DBO and TPA were mixed in a 1 :2 molar ratio plus an excess of 50% of TPA. Thus, 5g of DBO, 13g of TPA and 18g of methanoi were refluxed together at 68°C for 64 hours. Methanoi and excess amine were removed under vacuum at 70°C using a rotary evaporator. The result was a biphasic liquid which rapidly separated into two layers. The top layer was a colourless liquid (code name DC-2L0 which can easily be poured off from the bottom thick oily layer (code name DC-2S were examined by mass spectrometry. The results obtained using electro-spray mass specfroscopy showed that DC-2S contained the target molecule octane-l,8-di- tripentyl ammonium bromide formed through the reaction:

Br - R' - Br + 2(R)₃N ► (R)₃N⁺(R)₃.2Br^"

The new doubly charged dimeric tetraalkyl ammonium salt Octane- 1,8-di-tripentyl Ammonium Bromide (OTAB) has a formula weight of 726.91. The chemical structure of OTAB is shown below:

H_πC_{5 π} . 2Br^"

C₅H_U C₅H_π 1,8-Octane-di-Tripentyl Ammonium Bromide (OTAB) C38H82NBr2, f.w: 726.91

Example 2

Carbon dioxide Film Sensor using OTAB

3.63g of OTAB was dissolved in 12g (15.2mL) of methanoi. 4g of Ag₂O was added to the solution and stirred for four hours. The resulting 20% w/w methanolic solution of the hydroxide salt 1,8-Octane-di-tripentyl ammonium hydroxide (OTOAH) was collected by decantation.

O.lg of the pH indicator dye (m-cresol purple, thymol blue or xylenol blue) was dissolved in lOg of the 20% w/w OTAOH methanolic solution. Methanoi was evaporated using a rotary evaporator and 7.9g of tetrahydrofuran was added to form a 20:1% base: dye solution.

0.3g of the base:dye solution was added to lOg of 3% w/w polydimethyl silicone (PDMS) polymer solution and mixed before applying to a IPS filter paper.

Filter papers loaded with the sensor materials above showed a good response to 5% carbon dioxide and it is limited by the pH operating range of the dye. Adding a small amount (0.5-20 parts per hundred parts polydimethyl silicone) of polyethylene glycol (PEG) was again found to increase both the equilibrated sensitivity to CO₂ and the sensor response rate.

Samples with the above formulation were prepared with a loading of 20 phr of OTOAH, 1 phr of m-cresol purple and 2 drops of PEG (-18 phr). Example 3

Film behaviour under Long Term Exposure to Carbon dioxide

A fresh base;dye solution has been prepared using the conventional "two pot" formulation. Olg of m-cresol purple pH indicator dye was dissolved in lOg of 10% w/w methanolic solution of tetraoctyl ammonium hydroxide (TOAOH). The methanoi was replaced by tetrahydrofuran by evaporating the methanoi and adding 8.9g of tetrahydrofuran 0.36g of the above base:dye solution was added to lOg of 10% w/w polymer solution (PDMS in dichloromethane) along with 0.36g of 0.5% w/w PEG before casting on microscope glass slide.

The film was stored in an airtight glass jar with PURAFIL 100% carbon dioxide was passed into the jar to transform the film to the acidic state (yellow). The film was flushed with air after 24, 48, 96 and 800 hours and found to change colour to blue. The above result proved that exposing the film sensor to 100% carbon dioxide does not destroy the film mechanism provided that the film is well protected from other acid gases.

Example 4

The Film Shelf Life Test

Two film sensors were prepared in a similar fashion to the one described in the previous example. One of the above films was prepared without the addition of PEG. Both films were stored in an airtight glass jar with some PURAFIL for eighteen months. The films did not show any colour change.

Claims

1. A polymeric quaternary alkyl ammonium cation of the general formula I, or a salt thereof;

Ri R₃

-(CH₂)_n-N⁺-[-(CH₂)_n-N⁺-]_m-

I I

R₂ R₄

in which RΓÇ₧ R₂, R₃ and R₄, which may be the same or different, are each alkyl Cl to C20; m is an integer from 1 to 100; and n is an integer from 1 to 7.

2. A polymeric quaternary alkyl ammonium cation according to Claim 1 characterised in that RΓÇ₧ R₂, R₃ and R,, which may be the same or different, are each alkyl C5 to 10.

3. A polymeric quaternary alkyl ammonium salt according to Claim 1 characterised in that the anions of the salts are selected from the group halide, hydroxide, carbonate and tetrafluoroborate.

4. A polymeric quaternary alkyl ammonium salt according to Claim 3 characterised in that the halide is selected from fluoride, chloride, bromide or iodide.

5. A polymeric quaternary alkyl ammonium salt according to Claim 4 characterised in that the halide is bromide.

6. A polymeric quaternary alkyl ammonium salt according to Claim 3 characterised in that the anion is hydroxide.

7. A polymeric quaternary alkyl ammonium salt according to Claim 5 characterised in that the compound is 1,8-octane-di-tripentyl ammonium bromide.

8. A polymeric quaternary alkyl ammonium salt according to Claim 6 characterised in that the compound is 1,8-octane-di-tripentyl ammonium hydroxide.

9. A film formulation comprising a cation, or a salt thereof according to Claim 1 , in intimate mixture with a transparent film-forming polymer vehicle.

10. A film formulation according to Claim 9 characterised in that the transparent film-forming polymer vehicle is compatible with the indicator material, such that the latter does not exude or otherwise undergo phase separation over a prolonged period.

11. A film formulation according to Claim 9 characterised in that the transparent film-forming polymer vehicle is hydrolytically stable.

12. A film formulation according to Claim 9 characterised in that the transparent film-forming polymer vehicle is permeable to carbon dioxide.

13. A film formulation according to Claim 9 characterised in that the transparent film-forming polymer vehicle is organic solvent-soluble.

14. A film formulation according to Claim 13 characterised in that the transparent

polymer vehicle is selected from polyvinyl butyral, polyvinyl methyl ether, polymethyl methacrylate, ethyl cellulose and polystyrene.

15. A film formulation according to Claim 9 characterised in that the transparent film-forming polymer vehicle is water soluble.

16. A film formulation according to Claim 15 characterised in that the transparent film-forming polymer vehicle is selected from hydroxypropyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol (100% hydrolysed) and polypropylene glycol.

17. A film formulation according to Claim 9 characterised in that the transparent film-forming polymer vehicle is a polyurethane.

18. A film formulation according to Claim 9 characterised in that the transparent film-forming polymer vehicle is a silicone oligomer or polymer.

19. A film formulation accordmg to Claim 18 characterised in that the silicone oligomer or polymer is a polydimethyl silicone

20. A colorimetric sensor device comprising;

a polymeric quaternary ammonium cation, or a salt thereof, according to Claim 1 at least one pH sensitive dye; and a polymer in which the polymeric quaternary ammonium cation, or a salt thereof, is soluble.

21. A colorimetric sensor device according to Claim 20 characterised in that the pH sensitive dye is selected from thymol blue, m-cresol purple, xylenol blue and cresol-red.

22. A colorimetric sensor device according to Claim 20 characterised in that the polymer is described in PCT patent application no. WO96/24054.

23. A colorimetric sensor device according to Claim 20 characterised in that the device is in the form of film sensor and the film is provided with a support.

24. A colorimetric sensor device accordmg to Claim 23 characterised in that the support comprises a material selected from polypropylene sheet, a cellulose layer or a plastics foil material.

25. A colorimetric sensor device according to Claim 23 characterised in that the support comprises a silanised paper.

26. A colorimetric sensor device according to Claim 23 characterised in that the support comprises a glass substrate.

27. A method of carbon dioxide detection which comprises placing a sensor according to claim 20 in situ and observing a colour change.

28. An endotracheal intubation apparatus comprising a colorimetric sensor device according to Claim 20.

29. A method for determining the proper placement of an endotracheal tube which comprises inserting an endotracheal tube comprising a colorimetric sensor device according to Claim 20 into the trachea of a patient and observing a colour change.

30. A colorimetric sensor device substantially as described with reference to the accompanying examples.