Patent Grant
9671392
The present invention relates to a multisensor array for detection of analytes in the gas phase or in the liquid phase, comprising at least two different chemo-selective compounds. In particular the present invention relates to a sensor array for detection of organic compounds, inorganic compounds, anions and metal ions in the gas phase or in the liquid phase, comprising at least two different chemo-selective compounds. Said chemo-selective compounds are capable of individually changing physicochemical properties when exposed to analytes or analyte mixtures and these changes can be detected by a transducer or an array of transducers. The present invention does also relate to the use of at least two different chemo-selective compounds in a sensor array, a method for preparation of such sensor arrays and the use of said sensor arrays. Furthermore the present invention relates to methods for detecting and identifying analytes or mixtures thereof in the gas phase or in the liquid phase.
One of the most traditional and common technologies that involves detection and classification of volatile organic compounds in gas phase is an electronic nose or an electronic tongue for liquid sensing. The electronic nose is a device that combines a chemical-sensing and pattern-recognition systems; in nature it can in principle be the sensing organ of an animal like a nose of a bomb-sniffing dog. Conventional approaches to chemical sensors arrays have traditionally made use of a “lock-and-key” design, wherein a specific receptor is synthesized in order to strongly and highly selectively bind the analyte of interest. Nevertheless, the traditionally applied electronic nose technique is expensive and has certain limitations due to detection problems at low analyte concentrations, temperature and humidity requirements. Furthermore, the technical equipment can be rather heavy and difficult to move into new locations where detection is required.
Sensor arrays, in particular colorimetric sensor arrays, which involve an artificial nose having an array of at least a first dye and a second dye in combination and having a distinct spectral response to an analyte are well known in the prior art. Typical examples of sensor arrays comprising at least two different chemo-selective dyes, where the dyes are from the group of porphyrin, chlorin, chlorophyll, phthalocyanine, or salen, in particular metalated or non-metalated porphyrines and derivatives thereof are known for example from U.S. Pat. Nos. 6,495,102, 6,368,558 and 7,261,857 in which the sensor arrays are particular useful for detecting metal ligating vapors. US2000050839 describes an apparatus and method including a colorimetric array comprising porphyrinogen dyes to detect lung cancer via exhaled breath. US20080199904 describes an apparatus and method including a colorimetric array comprising porphyrinogen dyes to detect and identifying microorganisms. WO2010028057 describes a colorimetric array comprising of nanoporous pigments based on porphyrinogen dyes. A sensor device comprising porphyrinogen derivatives having binding affinity for explosives is known from WO2007132430.
The chemical diversity of the metalated or non-metalated porphyrines and the derivatives thereof described above is relatively limited and only well suited for the detection of metal ligating analytes. The porphyrinogen derivatives having high binding affinity for explosives suffers from a strong cross-reactivity with other electron-deficient guests like chloride ions (JACS, 2004, 126, 16296-16297) (JACS, 2006, 128, 2444-2451). Furthermore, the described sensor molecules are relatively complex molecules with a limited chemical diversity.
Also operational constraints for example environmental changes such as temperature, humidity and large number of interferants giving rise to false positives and false negatives due to too low sensitivity makes it highly desirable with a new class of sensor molecules to provide an improved sensor array in particular a more efficient and/or reliable sensor array.
To solve the above mentioned problems of the prior art an emerging strategy that is complementary to the conventional chemical sensing approach involves the use of less specific sensor molecules with a higher degree of cross reactivity. Such sensor arrays can potentially recognize specific molecules precisely and can be applied in many areas of research and industry, such as food quality analysis, medical diagnostics, explosives and toxins detection and environmental monitoring. For practical purposes, such sensing molecules should be relatively simple and cheap while at the same time allow for a large structural diversity.
The present invention relates to multisensory arrays for detection and/or identification of analyte(s) and mixtures thereof such as, for example, explosives, drugs, narcotics, chemicals poisonous, toxins, toxic or relatively toxic compounds, or illegal compounds, in the gas phase and in the liquid phase. By way of examples said arrays can be used to screen for relevant explosives in a complex background as well as to distinguish mixtures of volatile organic compounds distributed in the gas phase.
The sensing is based on at least two chemo-selective compounds of the hetero atom-containing compounds represented by the general structure I)
wherein
These compounds can change their physicochemical properties when exposed to the analyte(s) in gasses or liquids, and these changes can then be detected by a transducer. As will be explained later different transduction methods are foreseen. One example is a colorimetric sensor array where colour change in the visible spectrum of at least two compounds is used as the detection mechanism.
Such sensor arrays have a wide area of application: in military, police, industry, medicine or by civilians—indoor or outdoor tests. The sensor arrays are capable of detecting and identifying chemical compounds belonging to different classes, like amines, alcohols, carboxylic acids, ketones, sulphides, and thiols. The array can also be applied for screening of the spoilage and/or freshness of food, of vapour poisoning compounds in industry or houses, and for monitoring the environment.
The colorimetric sensor array according to the present invention is a rapid method for detection of analytes, in some applications the responses can be achieved within 30-60 sec. Another advantage of the present invention is that the colorimetric sensor array is an inexpensive approach, and can potentially be produced as single use disposables.
Thus, an object of the present invention relates to a multisensor array for detection of analytes or mixtures thereof in the gas phase or in the liquid phase, comprising at least two different chemo-selective compounds represented by the general formula I), wherein X1 to X4 as well as R1 to R4 have the above meanings, and the dashed bonds represent independently of each other either a single bond or a double bond.
In particular, it may be seen as an object of the present invention to provide a sensor array that solves the above mentioned problems of the prior art.
A second object of the present invention relates to use of at least two different chemo-selective compounds represented by the general formula I), wherein X1 to X4 as well as R1 to R4 have the above meanings and the dashed bonds represent independently of each other either a single bond or a double bond; in a multisensor array for detection of analytes and mixtures thereof in gas or liquid phase.
A third object of the present invention relates to a method for preparation of the multisensor array according to the present invention, wherein at least two different chemo-selective compounds having the general formula I) are immobilized on a solid support.
In a fourth object the present invention relates to use of the multisensor array according to the present invention for detection and/or identification of an analyte or mixtures thereof in gas or liquid phase.
In a fifth object the present invention relates to a method of detecting and identifying an analyte or mixtures thereof in a gas or liquid, comprising:
Although the present invention will be described in connection with specified aspect and embodiments, it should not be construed as being in any way limited to the presented aspects or embodiments. In the context of the claims, the terms “comprising” or “comprises” do not exclude other possible elements or steps. Also, the mentioning of references such as “a” or “an” etc. should not be construed as excluding a plurality. Furthermore, individual features mentioned in different aspect or claims, may possibly be advantageously combined, and the mentioning of these features in different aspect or claims does not exclude that a combination of features is not possible and advantageous. The different aspect and embodiments of the present invention may each be combined with any of the other aspects. These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter.
The sensor array according to the invention will now be described in more detail with regard to the accompanying figures. The figures show one way of implementing the present invention and is not to be construed as being limiting to other possible embodiments falling within the scope of the attached claim set.
The present invention will now be described in more detail in the following.
Thus, an object of the present invention relates to a multisensor array for detection of an analyte or mixtures thereof, such as organic compounds, inorganic compounds, anions and metal ions, in the gas phase or in the liquid phase, comprising at least two different chemo-selective compounds represented by the general formula I)
wherein
The mammalian olfactory system contains approximately 1000 different olfactory receptor genes and, upon odor stimulation, responses from many receptors are sent to the olfactory bulb and then to the olfactory cortex for processing. Furthermore, recent experiments have shown that the olfactory receptors are not highly selective toward specific analytes; in fact, one receptor responds to many analytes and many receptors respond to any given analyte. Pattern recognition methods are thus thought to be a dominant mode of olfactory signal processing. A multisensory array is an array of chemo-selective compounds applied on a solid support, simulating the mammalian olfactory system. Like the mammalian olfactory system the array has the capability to identify organic compounds, inorganic compounds, anions and metal ions, in the gas phase or in the liquid phase, because each chemo-selective compound is capable of individually changing physicochemical properties when exposed to analytes or analyte mixtures. These changes of physicochemical properties can be detected by a transducer or an array of transducers. For example, changes in colour can be detected either by transmission measurements or by reflection measurement using e.g. standard ccd cameras or flatbed scanner. Other transduction methods can measure the change in mass e.g. using cantilever arrays by change in resonance frequency, or acoustic wave devices, or quartz crystal microbalances, change in surface stress using cantilevers, change of surface potential using MOSFET arrays, change in conductivity e.g. using conductive polymer arrays, change in molecular vibrations using raman, surface enhanced raman, and infrared spectroscopy. The individual change of each chemo-selective compound in the array is then analyzed by pattern recognition methods to analyze, classify the analyte or analyte mixture.
Useful chemo-selective compounds of this invention include very simple compounds, like the compounds numbered 12, 13 and 20 as shown in Table 1 and in the examples section, which at the same time allow a very high structural diversity, which is also evident from Table 1. Furthermore, many compounds of this class are commercially available or can be synthesized by known methods. The number of potential chemo-selective compounds reported in the literature is in the thousands, matching the complexity of the mammalian olfactory system and making it possible to develop a universal sensor array for all purposes.
Said chemo-selective compounds are capable of individually changing physicochemical properties when exposed to analytes or analyte mixtures and these changes can be detected by a transducer or an array of transducers. Thus, chemo-selective compounds change physicochemical properties when exposed to the analyte(s) in gasses or liquids, and those changes can then be detected. Each of the compounds reacts chemo-selectively with the analyte via non-covalent interactions (host-guest interactions) and has its own fingerprint in response to the presented analyte. Therefore, by using an array of different chemo-selective compounds, analytes of very different nature, but also clearly closely related analyte molecules can be distinguished and detected. As illustrated in Example 4, more than one chemo-selective compound may be needed to distinguish between a false positive and a real positive. In the mentioned Example this is due to the presence of chloride anions existing together with DNT in the sample. In Example 4 we have used 15 different chemo-selective compounds to be able to distinguish between operational constraints like the environmental background from temperature effect and interferants like vapors from common organic solvents during the detection of the explosive DNT.
The present use of an array of chemo-selective compounds differs from conventional approaches to chemical sensors arrays which traditionally have made use of a “lock-and-key” design, wherein a specific receptor is synthesized in order to strongly and highly selectively bind the analyte of interest. The number of chemo-selective compounds needed to address operational constraints for example environmental changes such as temperature, humidity and other interferants giving rise to false positives and false negatives can be optimized according to the complexity of the particular application.
The chemo-selective compounds of this invention have capability to selectively recognize specific analytes; this recognition is a function of intermolecular interactions, basically weak, non-covalent interactions or donor-acceptor interactions. However, only weak, non-covalent interactions can occur between the hetero atoms of general formula I) and neutral target molecules like DNT, TNT or toluene. In order to increase sensing properties, different functional groups, such as dyes, can be incorporated by changing the substituents R1-R4 of the compounds of general formula I). These modifications will amplify the weak, non-covalent interactions to the respective analytes and increase/decrease the polarity, solubility and redox properties of compounds of the general formula I); the diversity of compounds is presented in Table 1 (below). For example, tetraTTF-calix[4]pyrrole (number 15 in Tab. 1) is one of the promising molecules that has good anion binding affinity and selectivity in polar solvents. The optically active calix[4]pyrrole-based sensor has already been applied for the detection of 1,3,5-trinitrobenzene, tetrafluoro-p-benzoquinone, tetrachloro-p-benzoquinone, p-benzoquinone, and 1,3,5-trinitrophenole.
The terms “gas phase” and “liquid phase” have their ordinary meanings. The liquid phase also includes heterogeneous suspensions of particles in a medium.
Thus, one aspect the present invention relates to a sensor array for detection of organic compounds, inorganic compounds, anions and metal ions in the gas phase or in the liquid phase, comprising at least two different chemo-selective compounds represented by the general formulas 1) and 2)
wherein
Another aspect of the present invention relates to a sensor array according to the present invention comprising at least fifteen different chemo-selective compounds represented by the general formula I), wherein X1, X2, X3, and X4 each independently represents a hetero atom selected from nitrogen being NH or substituted nitrogen, oxygen, sulfur, selenium, and tellurium; and R′, R2, R3, and R4 each independently represents hydrogen, halogen, or any organic or metal organic group; and the dashed bonds represent independently of each other either a single bond or a double bond.
In still another aspect the present invention relates to the sensor array according to the present invention comprising at least fifteen different chemo-selective compounds represented by the general formulas 1) and 2), wherein X1 to X4 as well as R1 to R4 have the above meanings.
In another aspect according to the present invention hetero atoms X1, X2, X3, and X4 of the general formulas I) and 1) and 2) each independently represents a hetero atom selected from nitrogen being NH or nitrogen substituted by C1-C4-alkyl or chlorophenylmethyl, oxygen, sulfur, selenium, and tellurium; and
The substituent groups such as C1-C4-alkyl, C1-C20-alkylsulfanyl and C1-C4-alkoxycarbonyl have their ordinary meaning as commonly used in the field of organic chemistry.
In another aspect according to the present invention the hetero atoms X1, X2, X3, and X4 of the general formulas I) and 1) and 2) each independently represents a hetero atom selected from oxygen, sulfur and selenium.
In another aspect according to the present invention the hetero atoms X1, X2, X3, and X4 of the general formulas I) and 1) and 2) each independently represents a hetero atom selected from oxygen and sulfur.
In another aspect according to the present invention the hetero atoms X1, X2, X3, and X4 of the general formulas I) and 1) and 2) each independently represents an hetero atom selected from sulfur and selenium.
In another aspect according to the present invention the hetero atoms X1, X2, X3, and X4 of the general formulas I) and 1) and 2) each represents a sulfur atom.
In another aspect according to the present invention the substituents R1, R2, R3, and R4 of the general formulas I) and 1) and 2) each independently may represent halogen. By halogen is meant fluorine, chlorine, bromide, and iodine.
In another aspect according to the present invention the substituents R1, R2, R3, and R4 of the general formulas I) and 1) and 2) each independently represents hydrogen or an organic group.
In another aspect according to the present invention the compounds are selected from general formula 1), wherein
In another aspect according to the present invention the compounds are selected from general formula 2), wherein
Some interesting compounds according to the present invention and its different aspects can be found in Table 1 below.
Methyl
CH3 Methyl
Methyl
Methyl
Methyl
Ethyl
Ethyl
In another aspect according to the present invention the compounds of the general formulas I) and 1) and 2) has a molecular weight below 1700, preferably below 1600 and more preferably below 1500. In still other aspects of the invention the molecular weight of the compounds can be low and even below 1000.
In still another aspect according to the present invention the compounds are selected from general formula 1), wherein the hetero atoms X1 to X4 are selected from sulphur or selenium; and
In still another aspect according to the present invention the compounds are selected from general formula 2), wherein the hetero atoms X1 to X4 are sulphur; and
As evident from the above the at least two chemo-selective compounds can be selected from the compounds having general formula I), 1) and 2), or most preferred from a mixture thereof.
In one aspect according to the present invention one of the at least two compounds is compound 1 of Table 1.
In another aspect according to the present invention one of the at least two compounds is compound 2 of Table 1.
In another aspect according to the present invention one of the at least two compounds is compound 3 of Table 1.
In another aspect according to the present invention one of the at least two compounds is compound 4 of Table 1.
In another aspect according to the present invention one of the at least two compounds is compound 5 of Table 1.
In another aspect according to the present invention one of the at least two compounds is compound 6 of Table 1.
In another aspect according to the present invention one of the at least two compounds is compound 7 of Table 1.
In another aspect according to the present invention one of the at least two compounds is compound 8 of Table 1.
In another aspect according to the present invention one of the at least two compounds is compound 9 of Table 1.
In another aspect according to the present invention one of the at least two compounds is compound 10 of Table 1.
In another aspect according to the present invention one of the at least two compounds is compound 11 of Table 1.
In another aspect according to the present invention one of the at least two compounds is compound 12 of Table 1.
In another aspect according to the present invention one of the at least two compounds is compound 13 of Table 1.
In another aspect according to the present invention one of the at least two compounds is compound 14 of Table 1.
In another aspect according to the present invention one of the at least two compounds is compound 15 of Table 1.
In another aspect according to the present invention the sensor array comprises at least two different compounds selected from compounds 1 to 15 of Table 1.
In another aspect according to the present invention the sensor array comprises all of the compounds 1 to 15 of Table 1. In another aspect the sensor array comprises all of the compounds 1 to 13 as well as at least two compounds selected from compounds 16 to 78 of table 1.
The sensor array according to the present invention with a plurality of chemo-selective compounds is by way of example suitable for detection of illegal drugs. Large amount of drug precursors smuggled around the world through various ways: aircrafts, by freight vehicles and container transport. This sensor can thus help to easily detect a variety of illegal chemicals and drugs, and drug precursors carried by individuals as well as hidden in mails, luggage and conveyance.
The sensor array according to the present invention can also be used to define the presence of bacteria on the surface of food samples. Food, such as meat and fish, are in fact excellent mediums for microbial growth due to high water content, the water soluble carbohydrates and non-protein nitrogen, favourable pH, and high levels of oxygen. The food manufacturing industry requires fast information regarding quality of raw material and commodities. In general, microbial food spoilage is a relatively saddening event, but if it has occurred then results of microbial activity can reveal themselves in different ways: products and by-products of microbial metabolism, pigments, gases, polysaccharides, flavours, and odours. The sensor array can in this contest provide rapid information about the presence of metabolically active microorganisms on the surface of food samples. Therefore, this sensor can be used as a simple and rapid tool since it is easy to use and can be provided at a low cost. Measurements using the sensor array according to the invention can be performed within 2 min or less. The sensor array of the present invention were applied to detect presence of bacteria in minced meat and fish samples as shown in the Example section. The working principle was based on the detection and identification of gases emanating by bacteria during their metabolism.
The sensor array according to the present invention can also be used for screening of most commonly used explosives and organic compounds in the real-time format in liquid phase. The main characteristics for the sensor array are based on such parameters as detection limit, time of the response and high selectivity. Those characteristics are very important and essential in order to prevent terroristic attacks, distribution of narcotics, illegal drugs or in the environmental control. The sensor survey can also be performed in liquid phase, for example in water or in organic polar solvents, and this can enhance the detection properties of the sensor array. The liquid phase is a good environment for screening of analytes in various concentrations. The signal of relevant changes in the sensor array can often be obtained faster in liquid phase than in gas phase.
Thus, a second object of the present invention relates to use of at least two different chemo-selective compounds represented by the general formula I), wherein X1, X2, X3, and X4 each independently represents a hetero atom selected from nitrogen being NH or substituted nitrogen, oxygen, sulfur, selenium, and tellurium; and R1, R2, R3, and R4 each independently represents hydrogen, halogen, or an organic or metal organic group; and the dashed bonds represent independently of each other either a single bond or a double bond; in a sensor array for detection of analytes and mixtures thereof in gas or liquid phase.
In one aspect the present invention provides use of at least two different chemo-selective compounds represented by the general formulas 1) and 2), wherein X1, X2, X3, and X4 each independently represents a hetero atom selected from nitrogen being NH or nitrogen substituted by C1-C4-alkyl or chlorophenylmethyl, oxygen, sulfur, selenium, and tellurium; and R′, R2, R3, and R4 each independently represents hydrogen, halogen, or an organic or metal organic group; in a sensor array for detection of analytes and mixtures thereof in gas or liquid phase.
In one aspect of the present invention the hetero atoms X1, X2, X3, and X4 each independently may be selected as indicated above.
In another aspect of the present invention the substituents R1, R2, R3, and R4 each independently may be selected as indicated above.
In another aspect of the present invention different combinations of the hetero atoms X1-X4 and substituents R1-R4 may be selected as indicated above.
In one aspect of the second object of the present invention the at least two different compounds are selected from compounds no. 1 to 15 of Table 1. In another aspect of the invention the compounds are selected from compounds no. 1 to 13 as well as at least two compounds selected from compounds no. 16 to 78 of table 1.
A third object of the present invention relates to a method for preparation of the sensor array according to the present invention, wherein at least two different chemo-selective compounds having the general formula I) are immobilized on a solid support. In another aspect the present invention relates to a method for preparation of the sensor array according to the present invention, wherein at least two different chemo-selective compounds having the general formulas 1) or 2) are immobilizing on a solid support. These at least two different chemo selective compounds are immobilized spatially separated and individually addressable.
It should be mentioned that the same methods can be used for preparation of the sensor arrays for both gasses and liquids and also that the same solid supports are applicable.
The solid support of the sensor array can be Si-based, such as poly- and mono-crystalline silicon, silicon dioxide, silicon nitride, silica, glass, controlled pore glass, silica gel, metallic such as gold, platinum, silver, titanium, vanadium, chromium, iron cobalt, nickel, copper, palladium, aluminum, gallium, germanium, indium, zinc, alloys like cadmium telluride and copper-indium-selenide, and metallic oxides, synthetic or natural polymers such as polystyrene, polyethylene, polypropylene, polyvinylacetate, polyvinylchloride polyvinylpyrrolidone, polyvinyldifluoride, polyacrylonitrile, polymethyl methacrylate, polytetrafluoro ethylene, polycarbonate, polyester, polyimide, cellulose, nitrocellulose, starch, polysaccharides, natural rubber, butyl rubber, styrene butadiene rubber, silicone rubber, epoxies like SU-8, polycyclic olefins' like Topas, photoresist materials, and conducting polymers like poly(3,4-ethylenedioxythiophene) (PEDOT), polyacetylene, polythiophene, polypyrrole, and polyaniline, carbon based such as glassy carbon, carbon paste, graphite, carbon nanotubes, and graphene. Preferred solid supports are silica gel, silicon dioxide, silicon nitride, gold, platinum, polyimide, nitrocellulose, polyvinyldifluoride, polyester, polypropylene, nylon, polytetrafluoro ethylene, polyamide, glassy carbon, carbon paste, graphite, corbon nanotubes, and graphene.
In yet another aspect of the present invention the at least two different chemo-selective compounds are immobilized on a solid support and their locations in the array are as illustrated in
In another embodiment of the present invention compounds 1 to 13 of Table 1 are immobilized on a solid support together with two other compounds selected from Table 1.
In gas phase, the array of chemo-selective compounds can be exposed to saturated vapours of analytes (e.g., acetone, acetic acid, DNT, formic acid, hydrochloric acid, methanol, ethanol, propanol, and toluene as described in example 4). Alternatively vapours can be passed over the array using a flow cell and a pump. Low concentrations of less volatile compounds like explosives can be detected using a sample pre-concentrator followed by heating of the sample bringing the vapours to the array.
In liquid phase, the array of chemo selective compounds can be immersed into the liquid, or liquid can be passed over the array using a fluidic system. For use in liquid phase special attention in the selection of chemo-selective compound will be to avoid bleeding of the compounds in contact with the liquid.
Thus, in a fourth object the present invention relates to use of the sensor array according to the present invention for detection and/or identification of an analyte or mixtures thereof in gas or liquid phase. Therefore, if no bleeding occurs in the liquid phase, the same sensor array can be used in both liquid and gas phase.
In a further aspect the present invention relates to use of the sensor array according to the present invention for detection and/or identification of an analyte or mixtures thereof such as a volatile organic compound or mixtures thereof in gas phase.
In one aspect the present invention relates to use of the sensor array according to the present invention for detection and/or identification of a volatile organic compound or mixtures thereof in gas phase. The gas phase may be ambient air or may be an inert carrier gas like nitrogen or argon. The array can also be useful in detection of and identification of volatile organic compounds in the presence of water vapor in air.
In another aspect of the present invention the analyte or mixtures thereof are amines, alcohols, carboxylic acids, ketones, sulphides, thiols, explosives, toxic compounds, toxins, drugs and drug precursors, narcotics, environmental poisons and pollutants, exhaust gasses from burning of fuels (NOx and SOx).
In another aspect of the present invention the volatile organic compound or mixtures thereof are amines, alcohols, carboxylic acids, aldehydes, ketones, sulfides, thiols, explosives, toxic compounds, toxins, drugs, narcotics, environmental poison and pollutants.
In another aspect of the present invention the sensor array can be used for screening of spoilage and/or freshness of food based on the detection and identification of gases emanating by bacteria during their metabolism.
In another aspect of the present invention the sensor array can be used for screening of vapour poisoning compounds in plastic materials and furniture in the gas phase.
For each application the chemo-selective compounds of the sensor array will be selected to address operational constraints for example environmental changes such as temperature, humidity and other interferants giving rise to false positives and false negatives. Each array can be optimized according to the complexity of the particular application.
In a fifth object the present invention relates to a method of detecting and identifying an analyte or mixtures thereof in a gas or liquid, comprising:
In one aspect the present invention relates to a method of detecting and identifying a volatile organic compound or mixtures thereof in a gas, comprising:
In one aspect the first and second measurements are performed by electrochemical measurements, photonic measurements, conductivity measurements, colorimetric measurements, etc., or by an array of different measurements. The changes of physicochemical properties of the chemo-selective compounds of the array can be detected by a transducer or an array of transducers. For example, changes in colour can be detected either by transmission measurements or by reflection measurement using e.g. standard ccd cameras or flatbed scanner. Other transduction methods can measure the change in mass e.g. using cantilever arrays by change in resonance frequency, or acoustic wave devices, change in surface stress using cantilevers, change of surface potential using MOSFET arrays, change in conductivity e.g. using conductive polymer arrays or graphene. The individual change of each chemo-selective compound in the array is then analyzed by pattern recognition methods to analyze, identify or classify the analyte or analyte mixture.
In another aspect according to the present invention analyzing a difference between the first and second measurements gives a fingerprint of the analyte(s) in the gas or liquid phase. The initial measurement will record the environmental background of interfering substances while the second measurement records the change caused by the presence of the analyte or analytes plus the background. Calculating the difference map between the two measurements will give the fingerprint of the analyte or analytes alone. When using a colorimetric technique as the transduction method, each compound in the array changes color. A change in a color signature indicates the presence of known or unknown analytes. Each chosen dye reacts chemo-selectively with the analytes of interest. Digital imaging of the dye array before and after exposure to the analytes creates a color difference map which composes a unique fingerprint for each analyte. In order to extract the color code from each dye the position of each dye on the image must be located. Each dye is represented using the red, green, and blue color scheme. In this model every color is provided as red, green, and blue color (RGB); RGB values are given in the 0-255 integer range. The minimum intensity of the color gives black (0;0;0) and maximum white color (255;255;255). After the dye has been located and converted to RGB values, the median value of each dye is calculated. The median instead of the mean is used in order to be more robust to noise and outliers.
In a sixth object of the invention relates to a method for detecting and identifying an analyte or mixtures thereof in a gas or liquid, comprising:
Another aspect of the invention relates to a method for detecting and identifying a volatile organic compound or mixtures thereof in a gas, comprising:
In another aspect of the present invention the analyte(s) are identified within 30-120 sec after exposure to the gas or liquid phase. In another aspect of the invention, the analyte(s) are identified in less than 30 sec. It is contemplated that the sensor sensitivity will be increased, by screening analytes in various concentrations and calculating the kinetics of relevant reactions.
In another embodiment of the present invention the analyte(s) are identified after several weeks of exposure to the gas or liquid phase.
It should be noted that embodiments and features described in the context of one of the aspects of the present invention also apply to the other aspects of the invention.
All patent and non-patent references cited in the present application, are hereby incorporated by reference in their entirety. The invention will now be described in further details in the following non-limiting examples and figure.
4,5-Bis[2-{2-(2-methoxyethoxy)ethoxy}ethylthio]-1,3-dithiole-2-thione (A) (see Lyskawa, J., et al., Tetrahedron, 2006. 62(18): p. 4419-4425) (4.50 g, 9.18 mmol) and 5-tosyl-1,3-dithiolo[4,5-c]pyrrol-2-one (B) (see Jeppesen, J. O., et al., Organic Letters, 1999. 1(8): p. 1291-1294) (1.91 g, 6.14 mmol) were suspended in anhydrous P(OEt)3 (100 mL) and placed in a preheated oil bath (135° C.). After 10 and 20 min., respectively, another ½ eq. of A (2×2.25 g, 2×4.59 mmol) was added and the reaction mixture heated for another
4 h. After cooling to room temperature, precipitation by addition of MeOH (150 mL), filtration and column chromatography [SiO2, CHCl3:EtOAc 2:1 v/v, Rf=0.2], was C obtained as a orange solid (4.51 g, 97%). Mp.: 46-48° C. MS (MALDI): m/z (%)={753 (M+, 28), 599 ([M-Ts]+, 100)}.
Compound C (4.48 g, 5.94 mmol) was dissolved in anhydrous THF (200 mL) and anhydrous MeOH (70 mL), and degassed with N2 for 20 min. To this solution was NaOMe i MeOH (25%, 3.21 g, 59.4 mmol) added and the reaction mixture heated to reflux for 1.5 h. After cooling to room temperature, H2O (250 mL) was added and the mixture extracted with CHCl3 (3×150 mL). The organic phases were combined, washed H2O (2×150 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was afterwards subjected to column chromatography [SiO2, CHCl3:MeOH 95:5 v/v, Rf=0.4] wherefrom D was obtained as a yellow oil (3.11 g, 87%). MS (MALDI): m/z (%)={600 (M+, 100)}.
Compound D (890 mg, 1.48 mmol) was dissolved in anhydrous DMF (125 mL) and degassed with N2 for 15 min., whereafter NaH (60% v/v suspension in mineral oil, 400 mg, 240 mg, 10.0 mmol) was added, whereby the color changed from yellow to orange. After 20 min., MeI (3.37 g, 23.7 mmol) was added to the mixture, resulting in a color change back to yellow. After 1.5 h, excess MeI was removed by stripping with N2 for 15 min., followed by dropwise addition of a sat. NaCl-solution (50 mL) until gas evolution no longer could be observed. After extraction with CHCl3 (250 mL), washing with sat. NaCl (2×250 mL), H2O (250 mL), and drying (MgSO4), the solvent is removed in vacuo. The resulting residue was subjected to column chromatography [SiO2, CHCl3:MeOH 98:2 v/v, Rf=0.3] wherefrom compound 9 was obtained as an orange oil (749 mg, 82%). MS (MALDI): m/z (%)={613 (M+, 100)}.
4,5-Bis(2-cyanoethylthio)-1,3-dithiole-2-thione (E) (see N. Svenstrup et al., Synthesis, 1994, 8, 809-812) (4.08 g, 13.4 mmol) was suspended in conc. HCl (320 mL) and heated to 40-42° C. for 3 h. The suspension was then poured into a mixture of ice/H2O (400 mL) and the product F isolated by filtration, washed with copious amounts of H2O and dried in vacuo. Recrystallization from 2-methoxyethanol/H2O yielded F as pale yellow needles (4.38 g, 96%). MS (EI): m/z (%)={340 (M+, 64), 166 (30), 72 (100)}.
4,5-Bis(2-amidoethylthio)-1,3-dithiole-2-thione (F) (0.63 g, 1.85 mmol) and 4,5-bis(2-(4-nitrophenyl)ethylthio)-1,3-dithiole-2-one (G) (see K. B. Simonsen et al., Angew. Chem., Int. Ed., 1999, 38 (10), 1417-1420) (1.33 g, 2.77 mmol) were suspended in a mixture of anhydrous degassed dioxane (250 mL) and triethyl phosphite (45 mL) and heated to reflux for 6 h. After cooling to room temperature and removal of the solvents in vacuo, the residue was washed with copious amounts of MeOH and dried under vacuum. The residue were purified by column chromatography [SiO2, I) CH2Cl2, II) CH2Cl2/MeOH 97:3, III) CH2Cl2/MeOH 94:6] yielding compound 3 as an orange solid (0.82 g, 57%). Mp: 191-193° C. MS (FAB): m/z (%)={772 (M+)}.
5-Tosyl-1,3-dithiolo[4,5-c]pyrrol-2-one (B) (see Jeppesen, J. O., et al., Organic Letters, 1999. 1(8): p. 1291-1294) (0.62 g, 2.00 mmol) and 4,5-bis(2-(4-nitro-phenyl)ethylthio)-1,3-dithiole-2-thione (H) (see D. Damgaard et al., J. Mater. Chem., 2000, 10, 2249-2258) (2.00 g, 4.00 mmol) were dissolved in triethyl phosphite (15 ml) and heated to 130° C. for 2 h. Then the reaction mixture was concentrated in vacuo and the residue purified by column chromatography [SiO2, CH2Cl2]. The red band was collected, the solvent removed in vacuo, and the residue recrystallized from CHCl3/petroleum ether (b.p. 60-80° C.) to give orange granules of compound 1, (0.24 g, 16%); Mp: 143-144° C. PDMS (m/z): 759.3.
5-Tosyl-1,3-dithiolo[4,5-c]pyrrol-2-one (B) (see Jeppesen, J. O., et al., Organic Letters, 1999. 1(8): p. 1291-1294) (0.75 g, 2.40 mmol) and 4,5-bis(methoxy-carbonyl)-1,3-dithiole-2-one (I) (see Baffreau, J., F. Dumur, and P. Hudhomme, Organic Letters, 2006. 8(7): p. 1307-1310) (3.20 g, 13.7 mmol) were mixed in o-xylene (80 ml) and heated to 130° C. Triethyl phosphite (8 ml) was added and the resulting reaction mixture stirred at 130° C. for 12 h, whereupon a second portion of I (1.6 g, 6.8 mmol) was added. The heating was continued another 12 h. Then the reaction mixture was concentrated in vacuo and the residue purified by column chromatography [SiO2, PhMe/EtOAc 1:0→4:1 v/v]. This afforded, after removal of the solvents in vacuo, the product 7 as a red oil that solidified upon standing. Recrystallization from EtOAc/petrol ether yielded 7 as red needles (0.58 g, 47%). Mp: 166-167° C. MS (EI): m/z (%)={513 (M+, 57), 358 ([M-Ts]+, 100)}.
2,3-Bis(2-cyanoethylthio)-6,7-bis(methoxycarbonyl)tetrathiafulvalene J (see K. B. Simonsen et al., Synthesis, 1996, 3, 407-418) (1.84 g, 3.75 mmol) was dissolved in anhydrous DMF (120 mL) and degassed with N2 for 15 min. CsOH.H2O (0.66 g, 3.94 mmol) was dissolved in anhydrous degassed MeOH (10 mL) and added dropwise over 1 h to the previous solution. After ended addition, the reaction mixture was stirred for additional 40 min., before 4,4′-bis(bromomethyl)-2,2′-bipyridine (K) (see Ashton, P. R., et al., Chemistry—A European Journal, 1998. 4(4): p. 590-607), dissolved in anhydrous DMF (15 mL), was added in one portion. After stirring overnight the solvent was removed in vacuo. The residue was redissolved in CH2Cl2 (250 mL) and washed with H2O (200 mL), sat. NaCl (4×200 mL) and H2O (200 mL) and dried (Na2SO4), before the solvent was removed in vacuo. The remaining residue was purified by column chromatography [SiO2, CH2Cl2/MeOH 100:2] affording compound 2 as a dark red compound (1.81 g, 92%). MS (FAB): m/z (%)={1054 (M+)}
1,3-Dihydro-N-tosyl-1,3-dithiolo[4,5-c]pyrrol-2-one (L) (see Jeppesen, J. O., et al., Organic Letters, 1999. 1(8): p. 1291-1294) (1.69 g, 5.4 mmol) and 4,5-bis(n-pentylthio)-1,3-dithiole-2-thione (M) (see B. M. Pedersen et. al., Eur. J. Inorg. Chem., 2006, 15, 3099-3104) (1.50 g, 5.00 mmol) were mixed in distilled triethyl phosphite (20 ml) and rapidly heated to 130° C. Two more portions of M (a 0.9 g, 3 mmol) were added after 10 and 20 min., respectively. The reaction was then stirred at 130° C. for 5 h and then left to cool to room temperature. MeOH (150 ml) was added and the precipitate formed was collected and washed with MeOH (3×20 ml) to give a yellow powder. This crude product was redissolved in a mixture of CH2Cl2/MeOH 1:1 (100 ml). The solution was reduced in vacuo to approximately half the volume and the precipitate that formed was collected as a yellow powder which was subjected to column chromatography [SiO2, PhMe/CH2Cl2 9:1 v/v]. This afforded compound 6 as orange needles (1.63 g, 50%), mp: 136-137° C.
2-(4,5-Bis[pentylthio]-1,3-dithiole-2-ylidene)-1,3-dithiolo[4,5-c]pyrrole (N) (see Jeppesen, 10., et al., The Journal of Organic Chemistry, 2000. 65(18): p. 5794-5805) (0.34 g, 0.75 mmol) was mixed with 0 (0.34 g 1.51 mmol), K3PO4 (0.34 g, 1.51 mmol), CuI (0.03 g, 0.08 mmol), and trans-cyclohexane-1,2-diamine (0.02 mL, 0.15 mmol) in anhydrous dioxane (2 mL) in an oven-dried Schlenk tube and heated to 110° C. on an oil bath for 24 h. After cooling to room temperature, EtOAc (100 mL) was added. The resulting precipitate was isolated by filtration and washed with EtOAc (50 mL). The compound P was used without further purification (0.13 g 33%).
To a suspension of NH4Cl (0.29 g, 8.65 mmol) in PhMe (5 mL) was AlMe3 (14 mL, 2 M in PhMe, 0.28 mol) added carefully and stirred for 1.5 h. To this was P (0.15 g, 0.27 mmol) in PhMe (10 mL) added and the mixture heated to reflux for 48 h. After cooling to room temperature, NH4Cl (3.15 g, 94.0 mmol) was added and followed by the very careful addition of 4 M NaOH (12 mL). The reaction mixture was then poured into 4 M NaOH (100 mL) and the organic phase isolated. After drying (MgSO4) and evaporation of the solvent in vacuo was the remaining residue subjected to column chromatography [SiO2, CH2Cl2, Rf=0.5] yielding compound 8 as a yellow powder (95.1 mg, 61%).
Sensor Array
Compounds 1-15 from the list of compounds in Table 1 were chosen. To prepare the sensor array, the chemo-selective compounds with given numbers 6, 8, 10, 13 and 15 were dissolved in 1,2-dichlorobenzene (Sigma, St. Louis, USA), and chemo-selective compounds with given numbers 1-5, 7, 9, 11, 12 and 14 were dissolved in DMSO (Sigma, St. Louis, USA) to obtain a final concentration of 1% (w/v). Stock solutions of the compounds were stored in brown flasks at room temperature. Immediately after preparation of the solutions, the chemo-selective compounds were immobilized on a solid support (Kieselgel 60F254, Merck KGaA, Germany). Position and structure of compounds, are shown in
The 15 solutions of the compounds described in Example 1 were used to prepare a miniaturized sensor array using a micro-contact spotting Spotbot2 instrument (Arrayit, Sunnyvale, Calif., USA) with a mounted SMP3 pin. Spot spacing was 150 μm. The pin has a flat surface, defined uptake channel which allows loading of 0.25 μL of a sample and produces spots of 110 μm in diameter. The solid support used here were both Kieselgel 60F254 membrane (Merck KGaA, Germany) and a nitrocellulose membrane (Schleicher & Schuell, Dassel, Germany). The volume per spot was not determined (a delivery volume of 600 pL was expected on a microscope slide surface). Pictures of the printed microarray were obtained by using an Olympus stereomicroscope with a mounted Olympus colored camera (Olympus, Center Valley, Pa., USA).
Different solid supports were used to prepare the sensor array according to the invention: Kieselgel 60F254 plates (Merck KGaA, Germany, PVDF membranes with hydrophilic properties (Millipore Corporation, Billerica, Mass., USA), nitrocellulose membranes (Schleicher&Schuell, Dassel, Germamy), polypropylene, polyester, nitrocellulose mixed ester, nylon, polyethersulfone, Teflon membranes, and glass fiber were from Stelitech (Sterlitech Corporation, Kent, Wash., USA). Chemo-selective compounds were manually deposited directly onto the solid support or deposited by using the micro-spotting technique as described in Example 1 and Example 2, respectively.
Analytes: acetone, acetic acid, 1,2-dichlorobenzene, 2,4-dinitrotoluene (DNT), formic acid, hydrochloric acid, methanol, propanol, toluene were obtained from Sigma (St. Louise, Mo., USA). Ethanol was ordered from Solveco Chemicals AB (Dramstadt, Germany). All chemicals were of analytical grade and used without further purification. Sensor arrays were prepared as described in Example 1. After scanning, each array was exposed to saturated analyte vapors at room temperature (DNT at 100° C.) for two minutes. Control measurements were performed at room temperature and elevated temperature of 100° C., respectively with ambient air. After exposure to analytes each array was scanned again. Each analysis was done in triplicates.
A colorimetric sensor array for detection of VOCs and DNT in a gas phase was designed using 15 chemo-selective compounds (compounds 1 to 15 of Tab. 1). Compounds were immobilized onto silica gel plates in the working volume of 1 μL. Since mass transport and time response are correlated values, saturated conditions of analytes (acetone, acetic acid, DNT, formic acid, hydrochloric acid, methanol, ethanol, propanol, and toluene) were prepared. Detection of acetone, acetic acid, formic acid, hydrochloric acid, methanol, ethanol, propanol, and toluene were performed at 24° C. DNT was detected at the elevated temperature of 100° C. Control measurements were performed at 24° C. and 100° C., respectively. Pictures were scanned twice through an ordinary flatbed scanner (Epson V750-M Pro Perfection scanner) first time immediately after immobilization of chemo-selective compounds and the second time after exposure to analytes. The experiment duration was 2 minutes for each analyte. Pictures were obtained at 600 dots per inch in the RGB color format. Results were analyzed by using MatLab software. Using the red, green and blue color scheme color changes for each compound were analyzed before and after exposure to the analyte. Color changes of each dye were analyzed using the red, green, and blue color scheme. In this model every color is provided as red, green, and blue color (RGB) with RGB values given in the 0-255 integer range. The minimum intensity of the color gives black (0,0;0) and maximum white color (255;255;255). After the dye was located and converted to RGB values, we calculated the median value of each. We used the median instead of the mean in order to be more robust to noise and outliers. A difference map was obtained from the values of red, green or blue colors after exposure minus the value of red, green or blue color before the exposure. Since the RGB color scheme does not allow negative values the absolute difference was taken. Further in order to enhance the visibility of the colors difference maps the RGB values were first scaled with a factor of 5 and then shifted from 5 to 10. The instances where the difference map (before scaling) resulted in a color value lower than 3 the pixel was rounded down to a color value of 0 (see Table 2 below).
By using the chemo-selective compounds we were able to apply the colorimetric sensor array for screening volatile organic compounds, like acetone, acetic acid, ethanol, formic acid, hydrochloric acid, methanol, propanol, and toluene, and also for probing explosives, like DNT in the gas phase. Color change patterns manifest the presence of a specific or given targets, in other words, the observed color change patterns indicate a particular vapour of the individual analyte or mixture of analytes. Digital images of arrays before and after exposure can be used for generating of the color difference map by pixel subtraction. A difference map is able to compose a unique fingerprint for each analyte or its mixture. For each analyte average color change profile was obtained and shown in
The resulting colorimetric sensor was used for the vapor analysis of acetone, acetic acid, ethanol, formic acid, hydrochloric acid, methanol, propanol, toluene, and DNT. The analysis demonstrates the familiar similarity in the response among compounds with common organic properties: alcohols, organic and inorganic acids, ketones and arenes. The strong signal was obtained in the presence of acids, the color-changes profile shows the significant different between inorganic and organic acids (
Since explosives have low vapor pressure at ambient conditions, DNT was heated up to 100° C. to increase the analyte vapor. The same working principle will be used in the commercialized sensor. The slide with the ordinary immobilized chemo-selective compounds was also heated up at the same elevated temperature; those results were used as a control. Obtained results are presented in the
To detect explosives, like DNT, RDX, HMX, TAPT, 15 chemo-selective compounds of general formula I were immobilized on the silica gel support in the working volume of 1 μL (
A difference map is able to compose a unique fingerprint for each explosive. To evaluate the color changes of chemo-selective compounds in the presence of explosives, the similar data analysis was performed as described above for VOCs. The changes in a color signature of the chemo-selective compounds indicate the presence of explosives in gas phase. By using the chemo-selective array it was possible to identify DNT (comp. no. 1, 2, 3, 5, 6, 8, 9, 11, 12, 13, 14, and 15), TATP (comp. no. 2, 4, 10, and 12), some compounds selectively changed color in the presence of RDX (no. 1, 4, 5, 7, 10, and 13) and HMX (comp. no. 4, 5, 10) (see Table 3 below).
The simple colorimetric sensor array can be useful for detection and/or identification of volatile organic compounds in air as the present molecules have capability for recognizing specific analytes as described supra.
In the present example the colorimetric sensor array with a plurality of chemo-selective compounds was shown to be suitable for detection of illegal drugs.
In similar order, again, 15 chemo-selective compounds of general formula I were immobilized on the silica gel support in the working volume of 1 μL. To increase the array sensitivity samples containing isosafrole (Sigma, St. Louis, USA) and phenylacetone (Sigma, St. Louis, USA) were heated up at the elevated temperature of 100° C. This technique was applied to elevate vapors emanating by illegal drugs.
The same detection principle was applied for identification of illegal drugs as has been described above for detection of explosives and VOCs. Herein, the colorimetric sensor was applied for detection of isosafrole and phenylacetone. Isosafrole and phenylacetone are precursors of illegal drugs which can be utilized for synthesis of “ecstasy”. Isosafrole is an aromatic organic chemical that has an odor similar to licorice and anise, and used for making soap and perfumes, as well as used as a preservative and antiseptic agent. Phenylacetone is an aromatic organic chemical with odor of anise. Phenylacetone can be used in production of pesticides and anticoagulants. However, phenylacetone has a strong effect on the sympathetic nervous system and can be used as an alternative material for synthesis of amphetamine and “ecstasy”. As used herein, the chemo-selective compounds were able to change color in the presence of isosafrole and phenylacetone. The representation of color changes in RGB format is presented in Table 4. The colorimetric sensor has shown a large response to the presence of phenylacetone (comp. no. 1, 3, 4, 5, 7, 9, 10) and for isosafrole (comp. no. 1, 4, 7, 9 and 13), respectively.
The colorimetric sensor array can be employed for effective and fast monitoring of narcotics. The colorimetric sensor array can be used as an alternative sensor for effective real-time survey of different types of illegal drugs, like for example LSD.
The colorimetric sensor array was applied for detecting LSD. The array was performed at elevated temperature of 100° C. In the array of 15 chemo-selective compounds the silica gel membrane was used as a supporting material. Chemo-selective compounds were applied in the working volume of 1 μL in order presented in
The RGB color format was used to extract data from the sensor; the results are presented in Table 4. The sensor showed a significant response wherein chemo-selective compounds were able to detect the presence of LSD in the gas phase (comp. no. 4, 8, 10, 14, and 15) (see Table 4 below).
The colorimetric sensor according to the present invention can be used to define the presence of bacteria on the surface of food samples as mentioned supra. The compounds of general formula I were applied to detect presence of bacteria in minced meat and fish samples.
Pork minced meat and Alaska Pollack fish were used in current experiments. Tested samples were kept at room temperature (approximately 24° C.) for 2 days, meanwhile control samples into a refrigerator at 4° C. for 2 days, respectively. Detection of vapours emanating by bacteria were performed at 24° C. Experiments were of 2 minute in duration. Pictures were scanned through an ordinary flatbed scanner (Epson V750-M Pro Perfection scanner) immediately after immobilization of chemo-selective compounds and after exposure of analytes. Pictures were obtained at 600 dots per inch in RGB color format. The similar data analysis was performed. It would appear that chemo-selective compounds were able to change color and detect food spoilage in samples. Color change results are presented in Table 5 below. According to the data analysis the chemo-selective compounds were able to detect the products of bacteria metabolism in pork minced meat (comp. no. 7) and Alaska Pollack fish (comp. no. 8 and 10) samples (Tab. 5).
The colorimetric sensor array can be also use for screening of most commonly used explosives and organic compounds in the real-time format in liquid phase. The signal of relevant reactions which depending on color changes can be obtained faster in liquid phase than in gas phase. Since the chemo-selective compounds have strong donor-acceptor properties it is important to evaluate the interaction between chemo-selective compounds, applied solvents and membrane stability.
For detection of DNT in liquid phase 15 chemo-selective compounds were immobilized on a solid support, a silica gel membrane, as shown in
Data obtained with the colorimetric sensor array has been statistically evaluated by using the principal component analysis (PCA) method. PCA is a simple, non-parametric method which is relevant to extract data among different analytes into the minimum number of dimensions. In order to apply this method the difference maps must be represented as a matrix. As described earlier, each difference map can be represented using 45 color numbers hence each difference map corresponds to a vector is a 45 dimensional space (each map contains 15 dyes and each dye yields 3 values). We then construct a data matrix where each column corresponds to a difference map. PCA was applied to this data matrix.
According to the statistical analysis the overlap in the response for different analytes is insignificant (
Although the present invention has been described in connection with the specified embodiments and aspect, it should not be construed as being in any way limited to the presented examples. The scope of the present invention is set out by the accompanying claim set.
This application is a U.S. National Phase Application of PCT International Application Number PCT/EP2011/055014, filed on Mar. 31, 2011, designating the United States of America and published in the English language, which is an International Application of and claims the benefit of priority to U.S. Provisional Application No. 61/319,449, filed on Mar. 31, 2010. The disclosures of the above-referenced applications are hereby expressly incorporated by reference in their entireties.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2011/055014 | 3/31/2011 | WO | 00 | 12/20/2012 |
| Publishing Document | Publishing Date | Country | Kind |
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| WO2011/121077 | 10/6/2011 | WO | A |
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| Number | Date | Country | |
|---|---|---|---|
| 20130096030 A1 | Apr 2013 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61319449 | Mar 2010 | US |
