QUATERNARY AMMONIUM SALTS, POLYMERIC FILM CONTAINING THEM AND COLORIMETRIC DEVICE

Abstract: There is described an oxygen substituted quaternary alkyl ammonium cation of formula (I), and salts thereof, in which R1, R2 and R3, which may be the same or different, are each alkyl C1 to 20; and m and n, which may be the same or different, are preferably an integer from 1 to 19. 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 oxygen substituted 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 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. WO96/24054. Known quaternary alkyl ammonium indicator cations, and their salts, tend to be mobile within a sensor film and can therefore be lost through migration. Migration places significant restrictions on the choice of sensor substrate (which must be compatible with organic polymers), further restricting the choice of polymers for sensor film formulation. We have now surprisingly found that the use of an oxygen substituted quaternary alkyl ammonium cation or salts thereof, provide an indicator dye which has improved compatibility with organic polymers, widening the choice of polymers available for sensor film formulation. According to the invention we provide an oxygen substituted quaternary alkyl ammonium cations of the general formula I, or a salt thereof; Ri I R 3 -N + -(CH 2 ) n -O-(Cr ) m -C^ I R? in which R,, R 2 and R 3 , which may be the same or different are each alkyl Cl to 20; and m and n, which may be the same or different, are each an integer from 1 to 19. It is preferred that the v ues of m and n, which may be the same or different, are each from 5 to 10, more preferably m and n together should have a total in the range offrom 4 to 10. 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. Particularly preferred salts are N,N,N-tripentyl-N-ethyl ethyl ether ammonium bromide and N,N,N-tripentyl-N-ethyl ethyl ammonium hydroxide. The cations of formula I, and salts 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. Alternatively, the transparent vehicle may be a film forming oligomer. 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 (the intended lifetime of the sensor). Thus the film-forming polymer should be volatile, e.g. at room temperature and the quaternary alkyl 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 preferably be substantially 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 methacrylate, ethyl cellulose and polystyrene. Examples of water-soluble film-forming polymers, which also have good resistance to hydrolysis, include hydroxypropyl 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 quaternary alkyl 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 w ) 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: R 9 -(O-R 10 ) x -(O-R u ) y -O-R 12 (I) R 9 -(CH 2 -(O-R 10 ) x -(O-R n ) y -O-R 12 ) p (II) R 9 -S-R 13 -(O-R 10 ) x -(o-R n ) y -O-R n (HI) (R 9 ) q -N(R I3 -(O-R 10 ) x -(O-R n ) y -O-R 12 ) r (TV) wherein R 9 and R 12 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, R 10 , R n and R 13 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 (TV) are the following: Polyalkylene glycols, such as polymethylene 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 dia ines. 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 polyvinylidene 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 trifiuoromethyl groups). It is particularly preferred that the silicone oligomer or polymer is a linear polydimethylsiloxane. The sihcone 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 polypropylene sheet, a cellulose layer or a plastics foil material. However, the sensors of the invention may comprise 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 (H 2 CO 3 ). Thus, dissociation of H 2 CO 3 to H + and HCO 3 " 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 according to the invention in situ and observing a colour change. The sensors of the invention have particul.ar utility in determining the proper placement of the 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 N,N,N- Tripentyl-n-Ethyl Ethyl Ether Ammonium Bromide Chemicals • Tri Pentyl Amine (TPA) 97%, fw: 227.44, bp; 81 -83°C, d: 0.788. • Bromoethyl Ethyl Ether (BEE) 90%, fw: 153.02, bp: 149-150°C, d: 1.357. • Methanol, d: 0.791. Experimental and Results 10.1 g of BEE, 18g of TPA and 20g of methanol were refluxed at 68°C for 24 hours. The result was an orange solution. Methanol and excess amine were removed under vacuum using the rotary evaporator at 70°C. The crude product consisted of a thick past of white crystals and orange oil. The oil was decanted and the white paste was washed with three portions of 100ml of ethyl acetate to give clean white fine crystals (product yield 25%). The product was then re-crystallised from petroleum ether (60- 80) to form needle shaped crystals. Electro-spray mass spectroscopy results confirmed that the needle shaped crystals were the target molecule oxygen substituted tetraalkyl ammonium bromide salt. N,N,N-Tripentyl-N-Ethyl Ethyl Ether Ammonium Bromide (TEEAB) with a molecular weight of 380.460. The chemical structure of the new ammonium salt is shown below: Ri I R 3 -N + -(CH 2 ) n -O-(CH 2 ) m -CH 3 . Br ' R, Wherein R„ R 2 and R 3 are pentyl and n and m are each 2. N,N,N-Tripentyl-N-Ethyl Ethyl Ether Ammonium Bromide (TEEAB) C 19; H 42; N; O; Br; FW:380.460. Example 2 Carbon Dioxide Film Sensor Using TEEAB 5.32g of TEEAB was dissolved in 17.6g (22.3ml) of methanol. 4g of Ag 2 O was added to the solution and stirred for one hour. The resulting 20% w/w methanolic solution of the hydroxide salt, TEEAOH was collected by decantation. 01-g of the pH indicator dye (m-cresol purple, Thymol blue or xylenol blue) was dissolved in lOg of the 20%w/w TEEAOH methanolic solution. Methanol 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. The filter papers loaded with the sensor materials above showed a good response to 5% carbon dioxide. Sensitivity to carbon dioxide is limited by the pH operating range of the dye selected. The sensitivity of the sensor films to carbon dioxide with respect to dye selected is in the order; m-cresol purple (pH range 7.4-9) < thymol blue (pH range 8.1-9.3) > xylenol blue (pH range 8.1-9.3). Adding a small amount of polyethylene glycol (PEG) 0.5-20 parts per hundred parts PDMS was found to increase both the equilibrated sensitivity to carbon dioxide and the sensor response rate. P36003WO.1

Claims: CLAIMS 1. An oxygen substituted quaternary alkyl ammonium cation of the general formula I, and salts thereof; Ri in which R„ R 2 and R 3 , which may be the same or different are each alkyl Cl to 20; and m and n, which may be the same or different, are an integer from 1 to 19. 2. An oxygen substituted quaternary alkyl ammonium cation according to Claim 1 characterised in that n and m are integers which together have a total in the range of 3. An oxygen substituted quaternary alkyl ammonium salt according to Claim 1 characterised in that the anion of the salt is selected from the group hahde, hydroxide, carbonate and tetrafluoroborate. 4. An oxygen substituted quaternary alkyl ammonium salt according to Claim 3 characterised in that the halide is selected from fluoride, chloride, bromide or iodide. 5. An oxygen substituted quaternary alkyl ammonium salt according to Claim 4 characterised in that the halide is bromide. 6. An oxygen substituted quaternary alkyl ammonium salt according to Claim 3 characterised in that the anion is hydroxide. 7. An oxygen substituted quaternary alkyl ammonium salt according to Claim 1 characterised in that the compound is N,N,N-tripentyl-N-ethyl ethyl ether ammonium bromide. 8. An oxygen substituted quaternary alkyl ammonium salt according to Claim 1 characterised in that the compound is N,N,N-tripentyl-N-ethyl ethyl ammonium hydroxide. 9. A film formulation comprising an oxygen substituted quaternary ammonium cation according to claim 1, or a salt thereof, in intimate mixture with a transparent film-forming polymer vehicle. 10. A film formulation according to Claim 9 characterised in that the transparent film-foπning polymer vehicle is compatible with the quaternary alkyl ammonium cation, or a salt thereof, 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 9 characterised in that the transparent film-forming 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 according to Claim 18 characterised in that the silicone oligomer or polymer is a polydimethyl silicone 20. A colorimetric sensor device comprising; a quaternary alkyl ammonium cation according to claim 1, or a salt thereof, at least one pH sensitive dye; and a film-forming polymer. 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 volatile polymer or oligomer 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 according 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 sensor device according to claim 18. 29. A method for determining the proper placement of an endotracheal tube which comprises inserting an endotracheal tube 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.

Inventors: ALBADRAN JAFAR, MCMURRAY NEIL HAMILTON, ALBADRAN, JAFAR, MCMURRAY, NEIL, HAMILTON
Applicants: ALBADRAN JAFAR, MCMURRAY NEIL HAMILTON, SENSORMETRIX INTERNATIONAL LIM, ALBADRAN, JAFAR, MCMURRAY, NEIL, HAMILTON, SENSORMETRIX INTERNATIONAL LIMITED
Application year: 1999
Main classification: C07C217
IPC codes: C07C217, G01N31