Patent Application
20100034961
The present invention relates to time-temperature indicator (TTI) systems comprising substituted spiroaromatic compounds with increased photostability as active material. The invention also relates to a method of manufacturing such a time-temperature indicator comprising the steps of (a) embedding in or atop a matrix said indicator compound; and (b) inducing the formation of a metastable state of said embedded indicator compound.
Time-temperature indicators, TTIs, are substrates for packaging of or attachment to perishable goods that are capable of reporting the partial or full time temperature history of any good to which it is thermally coupled.
Temperature abuse is one of the most frequently observed causes for predated goods spoilage. It is therefore important and desired to monitor the time-temperature history of such perishable goods, preferably, using inexpensive and consumer friendly means. Time temperature indicators are substances that are capable of visually reporting on the summary of the time temperature history of the substance, and consequently, of the perishable good it is associated with. Designed for the end user, time temperature indicators are usually designed to report a clear and visual Yes/No signal.
WO 99/39197 describes the use of photochromic dyes, based on a transfer reaction and embedded in the crystalline state, as active materials for TTIs. TTIs based on these materials are highly accurate and reproducible and can be charged using stimulating light. It further teaches that by placing a special filter atop the active substance most of the UV and visible spectrum of light can be filtered which prevents undesired re-charging of the TTI.
WO 2005/075978 also teaches TTIs based on photochromic indicator compounds. Specifically disclosed is
TTIs based on a photochromic indicator compound should, ideally, not be affected by surrounding light. Although there is a large selection of suitable filter systems, there is still a need for photochromic indicators which are improved in terms of photostability because existing filters cannot ensure complete protection against photobleaching and/or photodegradation of the indicator compound.
The problem underlying the present invention is therefore to provide a time-temperature indicator system having an increased photostability and which can furthermore allow the monitoring of the temperature of more and of less perishable products.
A novel time-temperature indicator (TTI) system that is based on specifically substituted spiroaromatic compounds as active material solves the above referenced problem.
A first embodiment of the present invention therefore relates to a time temperature indicator for indicating a temperature change over time, comprising at least one spiropyran indicator of formula (I)
wherein
With the proviso that
are excluded. (Claim 1)
The proviso is necessary because of the specific disclosure in WO205/075978 (Freshpoint), compounds 22 and 35 therein.
In one embodiment Y is phenyl, naphthyl, anthracen-9-yl, 9H-fluoren-9-yl (Claim 2)
Examples are:
Y is preferably a residue
Thus, a preferred spiroaromatic indicator is a compound of the formula (II)
wherein
With the proviso according to claim 1.
n in Ra is preferably 1, 2 or 3, for example, —CH2—, —(CH2)2—, —(CH2)3—; most preferred n is 1.
Examples for spiropyran indicators wherein Ra is —(CH2)2—, —(CH2)3 or —CH2—CH═CH—
An example for a spiropyran indicator wherein R5 and R11 form a ring is:
Ra is preferably CH2, and R11 is preferably H.
Thus a preferred spiropyran indicator is a compound of the formula (III)
wherein
With the proviso according to claim 1. (Claim 4)
The following table shows examples of compounds of the formula (III)
Halogen is F, Cl, Br or J, preferably F, Br, J, more preferably F. C1-C6alkyl is preferably methyl.
Best results have been received with the following spiropyrans:
The inventive TTI relies on a spiroaromatic compound which is reversibly photochromic. By virtue of its photochromic properties, the indicator compound can undergo photo-induced coloration by irradiation with photons of a specific energy range (conversion of the second isomeric form into the first isomeric form), the coloration being followed by a time- and temperature-dependent decoloration (conversion of the first isomeric form into the second isomeric form). The coloration of the indicator compound can take place at a defined time-point, preferably, for example, immediately after printing onto a substrate, which is especially the packaging of a perishable material.
It is preferred that the spiropyran compound as the reversibly photochromic active material of the TTI is in a crystallite form.
For example, the initially colorless indicator compound is irradiated with light, preferably UV light or near-UV light, whereupon an isomerization within the indicator compound (conversion of the second isomeric form into the first isomeric form) and an associated indicator compound coloration takes place. Such a photo-induced isomerization then proceeds as a function of time and temperature in the other direction again, so that the indicator is successively decolorized.
In each spiropyran compound exist at least two distinct isomeric forms, at least one open form and at least one cyclic isomeric form that can be converted into each other by valence isomerization:
Suitable active materials exhibit the following characteristics:
The active material of the present invention may be in the form of a crystal or a polycrystalline powder, in which the forward and reverse reactions take place or alternatively may be in a form of any other condensed phase such as a glass, a polymer solution or attached to a polymer, or in the form of a liquid or a solution.
The synthesis of the spiroaromatics used in the TTI according to the present invention, may be prepared according to synthetic routes known in the literature.
In yet another aspect of the present invention, there is provided a method for the manufacture of a TTI comprising an active material including at least one of the spiroaromatic indicator compounds described above, said method comprising the steps of
In one embodiment, the method further comprises the step of covering the time-temperature indicator with a cover support, designed to avoid photo recharging and/or photo bleaching. (Claim 6)
Depending on the specific application, a spiroaromatic compound having the required behavior may be chosen. Most of the above systems and all of the examples are characterized in that a non-colored or faintly colored thermodynamically stable state and at least one colored metastable state is used. Yet, these molecules are characterized by a relatively high optical quantum yield for the activation process turning the molecules colored and a substantially low optical quantum yield for the time and temperature dependent reaction process turning the molecules discolored. In the colored state, only negligible effect is found to any stimulus other than temperature. The activation process of the inventive TTI includes a ring opening step and the discoloration process is preferably accompanied with a ring closure.
The metastable state of the compounds used with the TTIs of the present invention may be achieved by one of the various stimuli mentioned hereinabove. In one embodiment, the metastable state is generated by photonic induction, wherein a matrix embedded with the substance is positioned or passed under a light source, emitting light of a wavelength and intensity suitable for photoexcitation, such as UV. The exposure to the light is terminated when the embedded substance changes its color to a color indicative of the formation of the metastable state at a pre-fixed quantity.
In another embodiment, the metastable state is achieved by pressure induction. In this procedure, the matrix embedded with and/or atop the substance is passed between two bodies, such as metal rolls, which apply pressure onto the surface of the matrix thereby inducing the formation of the metastable state. By adjusting the time and pressure imparted by the bodies to the active material, it is possible to control the degree of conversion from a stable state to a metastable state in the TTI active matrix.
In yet another embodiment, the metastable state is achieved by thermal induction. In this particular induction process, the matrix embedded with the substance to be induced is heated to temperatures normally below the melting point of said substance. The heat may be applied by any method known such as, but not limited to, a thermal transfer printing head. In one specific case, the heat is applied to the matrix while being passed through two heated metal rolls. In this case, the pressure applied to the surface is not capable itself of inducing the formation of the metastable state, but serves merely to ensure controlled thermal contact between the heaters and the sample. The metastable state is achieved as a result of the heat transfer from the heaters, i.e., the metal rolls, which are in contact with the matrix and the matrix itself.
However, there may be instances where the use of any combination of pressure, light and thermal inductions may be desired or necessary. It is therefore, a further embodiment of the present invention, to achieve the metastable state of the substances to be used with the TTIs of the present invention, by a combination of stimuli.
The support matrix used in the present invention may be a polymer such as PVC, PMMA, PEO polypropylene, polyethylene, all kinds of paper, all kinds of printing media or the like or any glass-like film. The active indicator may be introduced into and/or atop a matrix substrate such as polymers, glass, metals, paper, and the like, and may take on in the matrix any form that may permit reversibility of the induced chromic process. Such forms may be or result from indicator-doping of the matrix, sol-gel embedment of the indicator in the matrix, embedment of the indicator as small crystallites, solid solution and the like.
In one case, the depositing of the active material in the process of producing the TTI of the present invention is by transforming it into a printable ink that is suitable for printing using any of the printing methods known in the art, e.g., ink jet printing, flexo printing, laser printing and the like.
In another specific embodiment, the active indicator is embedded in the matrix in the form of small crystallites. In yet another specific embodiment, the active indicator is embedded in the packaging material of the goods.
The time temperature indicator according to the present invention is preferably packaged and/or attached to perishable items, especially to pharmaceuticals, biologicals or food items.
In another embodiment, the present invention also relates to a method of time temperature indication comprising the steps of
The adoption of said original state is visualized by a change of color based on the color difference between said metastable and original state. (Claim 8)
In a preferred embodiment of the present invention, the indicator compound as the active material of the time-temperature indicator is provided in an ink formulation, which is directly printed onto said packaging material or label. (Claim 9)
In another embodiment, the indicator compound is part of a thermal transfer (TTR) ink composition and is transferred to the printed surface by applying heat to the TTR layer.
In a specific embodiment, the present invention also relates to a method of determining the quality of ageing- and temperature-sensitive products, which comprises the following steps:
When ink-jet printing is used, the procedure is advantageously as follows:
In Step a), a time-temperature integrator comprising at least one spiropyran indicator compound as defined above, is applied by means of ink-jet printing to the substrate, especially to the packaging of ageing- and temperature-sensitive products or to labels that are applied to the packaging.
In a preferred embodiment, in Step a) it is possible additionally to apply, by means of ink-jet printing, a reference scale which reproduces the change in the color of the indicator as a function of time, and it is possible to apply, preferably in black ink, further text (or information), such as an expiry date, product identification, weight, contents etc.
Step a) is followed by Step b), activation, especially photo-induced coloration of the indicator compound. The photo-induced curing of the binder advantageously includes the photo-induced coloration of the indicator.
If desired, following Step b), an irreversible photo-sensitive indicator can be applied as tamper-proofing in the form of a covering over the time-temperature integrator. Suitable irreversible indicators include, for example, pyrrole derivatives, such as 2-phenyl-di(2-pyrrole)methane. Such a material turns irreversibly red when it is exposed to UV light.
Step c) is followed by the application of a protector, especially a color filter, which prevents renewed photo-induced coloration of the reversible indicator. In the case of UV-sensitive indicators, there come into consideration yellow filters, which are permeable only to light having typical wavelengths that are longer than 430 nm. Advantageously the protective film, that is to say the color filter, can likewise be applied by means of ink-jet printing.
Suitable filters are disclosed in the International application EP2007/060987, filed Oct. 16, 2007. Disclosed therein is a composition comprising at least one ultraviolet light and/or visible light absorbing layer which is adhered to an underlying layer containing a photo-chromic colorant,
which photochromic colorant is activated by exposure to UV light to undergo a reversible color change, which color reversion occurs at a rate that is dependent on temperature, wherein the light absorbing layer comprises a binder,
from 1 to 60% by weight based on the total weight of the layer of an ultraviolet light absorber selected from the group consisting of hydroxyphenylbenzotriazole, benzophenone, benzoxazone, α-cyanoacrylate, oxanilide, tris-aryl-s-triazine, formamidine, cinnamate, malonate, benzilidene, salicylate and benzoate ultraviolet light absorbers.
The time-temperature clock can be started at a defined desired timepoint. Decoloration is preferred for consideration according to the invention, but the use of an indicator in which the coloration process forms the basis of the time-temperature clock is also conceivable.
The actual determination of the quality of ageing- or temperature-sensitive products is preceded by the activation of the indicator in Step b). At a later timepoint, the degree of time- or temperature-induced decoloration is then measured and the quality of the product is inferred therefrom. When an evaluation is made with the aid of the human eye, it may be advantageous to arrange e.g. alongside or below the substrate a reference scale which allocates a certain quality grade, a certain timepoint etc. to a certain degree of decoloration.
When the quality of the product is determined by evaluating the degree of decoloration or coloration, it is therefore preferred to use a reference scale.
By means of a reference scale printed with the time-temperature integrator, absolute determination of quality grades is possible. The time-temperature integrator and the reference scale are advantageously arranged on a light-colored substrate in order to facilitate reading.
Suitable substrate materials are both inorganic and organic materials, preferably those known from conventional layer and packaging techniques. There may be mentioned by way of example polymers, glass, metals, paper, cardboard etc.
The substrates are suitable for use as packaging materials for the goods and or for attachment thereto by any method known. It should be understood, that the indicators of the present invention may also be applicable to and used in the food industry, and essentially be similarly effective to other goods that may be used in the pharmaceutical or medical fields.
The substrate can simultaneously form the packaging material for the perishable products or it can be applied to the packaging material, for example in the form of a label.
Another embodiment of the present invention concerns a packaging material or a label that comprises a time-temperature indicator as described above. (Claim 10)
In yet another embodiment, the present invention also relates to a high molecular weight material that comprises at least one spiroaromatic indicator as described above.
The high molecular weight organic material may be of natural or synthetic origin and generally has a molecular weight in the range of from 103 to 108 g/mol. It may be, for example, a natural resin or a drying oil, rubber or casein, or a modified natural material, such as chlorinated rubber, an oil-modified alkyd resin, viscose, a cellulose ether or ester, such as cellulose acetate, cellulose propionate, cellulose acetobutyrate or nitrocellulose, but especially a totally synthetic organic polymer (thermosetting plastics and thermoplastics), as are obtained by polymerisation, polycondensation or polyaddition, for example polyolefins, such as polyethylene, polypropylene or polyisobutylene, substituted polyolefins, such as polymerisation products of vinyl chloride, vinyl acetate, styrene, acrylonitrile, acrylic acid esters and/or methacrylic acid esters or butadiene, and copolymerisation products of the mentioned monomers, especially ABS or EVA. From the group of the polyaddition resins and polycondensation resins there may be mentioned the condensation products of formaldehyde with phenols, so-called phenoplasts, and the condensation products of formaldehyde with urea, thiourea and melamine, so-called aminoplasts, the polyesters used as surface-coating resins, either saturated, such as alkyd resins, or unsaturated, such as maleic resins, also linear polyesters and polyamides or silicones. The mentioned high molecular weight compounds may be present individually or in mixtures, in the form of plastic compositions or melts. They may also be present in the form of their monomers or in the polymerised state in dissolved form as film-forming agents or binders for surface-coatings or printing inks, such as boiled linseed oil, nitrocellulose, alkyd resins, melamine resins, urea-formaldehyde resins or acrylic resins.
In order to better understand the present invention and to see how it may be carried out in practice, preferred embodiments will now be described, by way of non-limiting examples.
General Syntheses of Monomeric Spiropyrans
In a first step a solution of an optionally substituted 2,3,3-trimethylindolenine 1 and a substituted alkylphenyl bromide 2 (preferably substituted benzylbromide) are reacted.
In a separate step a substitued nitrosalicylaldehyde 5 is prepared
In the next step compound 3 is reacted with compound 5 to obtain
The preparation of some compound is described in detail. All compounds of formula (I) may be prepared in a similar manner.
A solution of 2,3,3-trimethylindolenine (5.0 g, 31.4 mmol) and 4-fluorobenzylbromide (3.0 g, 15.7 mmol) in dry toluene 30 ml was stirred overnight at 80-85° C. The mixture was cooled to room temperature, filtered through a glass filter, washed with ether and dried under reduced pressure. The crude product was dissolved in CH2Cl2 treated with 5% NaOH(aq) under stirring for 30 minutes. The organic phase was separated, dried over Na2SO4, passed through a short alumina column in Hexane-CH2Cl2 50%, evaporated (cooling under nitrogen) giving rise to a corresponding free base, which was immediately dissolved in 10 ml ethanol containing a few drops of Et3N.
A solution of 1-(4′-fluorobenzyl)-3,3-dimethyl-2-methylene-indoline ((2.7 g, 10.0 mmol) and 2-hydroxy-3-methoxy-5-nitrobenzaldehyde (3.6 g, 13.0 mmol) was refluxed in 25 ml ethanol for 2 h, cooled to room temperature, filtered, triturated with 1% Et3Naq, washed with water, crystallized from ethanol, dried under reduced pressure. Yield: 3.0 g, 66.5%
A solution of 2,3,3-trimethylindolenine (2.5 g, 12.1 mmol) and 2,4-difluorobenzylbromide (2.1 g, 13.3 mmol) in 15 ml toluene was stirred for 12 h at 90° C. under nitrogen, cooled to room temperature, a solid (indolenine hydrobromide) was filtered, washed with ether. Mother liquid was evaporated under reduced pressure; a residue was dissolved in dichloromethane, treated with 5% NaOH under stirring for 30 min. The organic phase was separated, dried over Na2SO4, passed through a short alumina column in Hexane-CH2Cl2 (1:1), evaporated (cooling under nitrogen). The corresponding free base was immediately dissolved in 10 ml ethanol containing a few drops of Et3N.
3-methoxy-5-nitrosalicylaldehyde (0.59 g, 3.0 mmol) was added to a solution of 1-(2′,4′-difluorobenzyl)-3,3-dimethyl-2-methylene-indoline (1.0 g, 2.73 mmol) under stirring, and the reaction mixture was refluxed for 30 min. The reaction mixture was cooled to room temperature, filtered through glass filter; the solid product was washed with ethanol, triturated with 1% Et3N(aq), crystallized from ethanol, giving rise to the title compound as a yellowish powder. Yield 0.5 g, 39.4%
A solution of 2,3,3-trimethylindolenine (3 g, 12.3 mmol) and 4-(trifluoromethyl)benzyl bromide (2.35 g, 14.8 mmol) was stirred under nitrogen in 20 ml toluene for 24 h at 90° C. The mixture was cooled to room temperature, evaporated under reduced pressure, a residue was dissolved in CH2Cl2 and treated with NaOH(aq) 5% for 45 min. The organic phase was separated, dried over Na2SO4, chromatographed through a short alumina column in hexane-CH2Cl2 (1:1). The solvent was evaporated (cooling under nitrogen), giving rise to 151(2.9 g, 9.1 mmol), as a free base which was immediately dissolved in 45 ml ethanol containing a few drops of Et3N.
3-methoxy-5-nitrosalicylaldehyde (1.8 g, 9.1 mmol) was added to the solution and the reaction mixture was refluxed for 50 min. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, a residue was chromatographed on a short alumina column, eluent: hexane-CH2Cl2 (10-40%). The product was crystallized from ether-hexane, dried in vacuo. Yield 1.35 g, 19.7%
A solution of 2,3,3-trimethylindolenine (1.8 g, 11.5 mmol) and 4-(trifluoromethyl)benzyl bromide (2.4 g, 9.6 mmol) was stirred under nitrogen in toluene (20 ml) for 24 h at 90° C. The mixture was cooled to room temperature and evaporated under reduced pressure, the residue was dissolved in CH2Cl2 and stirred with NaOH(aq) 5% for 45 min. The organic phase was separated, dried over Na2SO4, passed through a short alumina column in hexane-CH2Cl2 (1:1). The solvents were evaporated (cooling under nitrogen) to afford the title indoline as a free base (1.27 g, 3.80 mmol), which was immediately dissolved in 45 ml ethanol containing a few drops of Et3N and subjected to the next step.
3-methoxy-5-nitrosalicylaldehyde (0.79 g, 4.00 mmol) was added to the solution under stirring, and the reaction mixture was refluxed for 30 min. The reaction mixture was cooled to room temperature, evaporated to dryness, purified by column chromatography on alumina, eluent: hexane-CH2Cl2 (5-50%). The product was crystallized from ether-hexane. Yield 0.53 g, 27.2%.
A solution of 4-methoxy phenyl-hydrazine hydrochloride (12.0 g, 68.7 mmol) and methyl isopropyl ketone (5.92 g, 7.35 ml, 68.7 mol) in 100 ml of ethanol(abs.) was refluxed for 2 h. The mixture was filtrated through a glass filter and the solvent was evaporated. A residue was extracted with dichloromethane, treated with 5% NaOH, dried over NaOH (pellets), passed through alumina pad, evaporated to dryness to give the corresponding indolenine. Yield 12.7 g, (98%). The product was used directly in the following step without further purification.
A solution of 5-methoxy-2,3,3-trimethyl-indolenine (3.8 g, 20.1 mmol) and 4-trifluoromethyl-benzylbromide (4.8 g, 20.1 mmol) in 20 ml dry toluene was stirred at 80-85° C. overnight, cooled to room temperature, the solvent was removed under reduced pressure, a residue was dissolved in CH2Cl2 and stirred with NaOH(aq) 5% for 30 min. The organic phase was separated, dried over Na2SO4, passed through a short alumina column in hexane-CH2Cl2 (1:1). The solvents were evaporated (cooling under nitrogen), giving rise to a free base 257 (2.8 g, 8.0 mmol), which was immediately dissolved in 40 ml ethanol containing a few drops of Et3N.
A solution of 3-methoxy-5-nitrosalicylaldehyde (0.9 g, 4.6 mmol) and free base 257 (1.6 g, 4.6 mmol) in ethanol (20 ml) was refluxed for 50 min. The reaction mixture was cooled to room temperature, filtered. A solid product was washed with ethanol, dried on the glass filter, dissolved in dichloromethane, passed through a short alumina column. The solvent was evaporated under reduced pressure and the residue was crystallized from ethanol, dried in vacuo. Yield 1.3 g, 54.2%
Samples of the pigment were incorporated in identical water based ink, dispersed using a mill under the same conditions. The ink was printed on the same paper substance and dried at room temperature for 24 hrs. The samples were placed on 5 mm glass plates that served as a thermal reservoir and charged using the same light source (TLC lamp 365 nm). Two identical samples were prepared and charged from each ink. One system was placed in the dark at 0 C while the other was exposed to filtered light (cutoff filter 455 nm) of a fluorescent lamp (“OSRAM” DULUX S G23, 900 Im, 11W/840), distance of 30 cm). The samples were measured using a colorimeter (Eye One GretagMacbeth). The CIE Lab values of the charged label that was kept in the dark were compared to the values of an identical label that was exposed to photobleaching light. As is evident from the following graphs, 3-methoxy group on the nitrophenyl group consistently reduce the photosensitivity of the colored species. Similarly, the presence of a heavy atom produces the same desired effect.
Procedures for the Ink Preparation
Water based ink composition: 10% TTI
Solvent based ink composition 10% TTI
Photobleaching Table O° C.
The CIE Lab values of the charged label that was kept in the dark were compared to the values of an identical label that was exposed to photobleaching light.
Preparation of compound 135 (State of the art compound, compound 35 of WO2005/075978)
1-(4′-fluorobenzyl)-3,3-dimethyl-2-methylene-indoline (62) was prepared as described in the procedure of compound (77) (vide supra).
2-hydroxy-6-methoxy-benzaldehyde (3.0 g, 6.57 mmol) in acetic acid (6 ml) was stirred in an ice bath at 5° C. Fuming nitric acid (10 ml, 15.2 g, 241 eq) was added dropwise at such rate that the temperature did not exceed 10° C. The mixture was stirred for 1 h at 25° C. Then, the solution was poured into ice-water (250 ml) under vigorous stirring. The dark red precipitate formed thereby was filtered through a glass sinter, washed with 1M HCl (20 ml), dried under reduced pressure, dissolved in CH2Cl2, and chromatographed through a silica pad giving rise to 3.8 g of crude yellow product. The product was re-crystallized from ethanol, dried under vacuum. Yield 0.6 g (15.4%)
6-methoxy-3-nitrosalicylaldehyde (0.45 g, 2.31 mmol) was added to a solution of 1-(4′-fluorobenzyl)-3,3-dimethyl-2-methylene-indoline (0.6 g, 2.24 mmol) in 15 ml ethanol. The mixture was refluxed for 1.5 h, cooled to room temperature, concentrated under reduced pressure to a 6 ml volume, filtered, washed with ethanol, recrystallized from ethanol. Yield 0.52 g (52.0%).
| Number | Date | Country | Kind |
|---|---|---|---|
| 07100411.3 | Jan 2007 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2007/064594 | 12/28/2007 | WO | 00 | 9/16/2009 |
