Biocompatible photoinitiators based on poly‐α‐ketoesters

Abstract

Migration of photoinitiators and their photoproducts are a major problem when it comes to food packaging or applications in the medical sector. Frequent coincidence with leachables and humans can be problematic, especially over time. Therefore, a new class of biocompatible photoinitiators, the aliphatic α-ketoesters, were selected to be immobilized. Biocompatibility and low leaching were achieved using the metabolite α-ketoglutaric acid. Immobilization of the photoinitiator is obtained via a macromolecular or copolymerizable approach. Today, a huge amount of coatings for everyday used items, like transparent food packages, thin foils, paints, and different car part finishes, are manufactured via curing of liquid resin formulations.1-3 Radical photopolymerization is the fastest growing curing technique,4 with a continuously increasing number of applications. Photoinitiators are the key component for every photopolymerizable formulation. After exposure to UV-light of specific wavelengths, the molecules can either react mono- or bimolecular depending on structure. Mono-molecular reaction mechanisms are called Type I and are based on direct absorption of a photon with subsequent cleavage of the molecule. In case of a bimolecular mechanism, with a combination of an initiator and coinitiator, the system reacts according to Type II. Hydrogen abstraction or electron/proton transfer from the coinitiator to the photoinitiator occurs and the generated radicals can initiate the polymerization.5 A major drawback in photopolymerizable systems is the large amount of unreacted photoinitiator in the cured polymer material.6-8 Due to the high conversion rates in a very short time, only a few initiator molecules are able to covalently bind to the growing polymer network. This could be solved by irradiating for a very long period of time or using small amounts of initiator. For industrial scale applications, short exposure times to UV-light to ensure high throughput are necessary. To still provide a reasonable conversion, and due to the fact that most photoinitiators are very cheap, an increased percentage of photoinitiator is usually used. Combined with exposure to radiation sources like UV-light or sunlight, a variety of photo-products are generated. They cause odor, volatile compounds such as benzaldehyde, yellowing of the material and migration of all byproducts out of the polymer matrix over time.6-9 Migration is especially problematic when protective and decorative coatings are applied in the field of food packaging, health care, and other all day use items, which can come in contact with humans. Photoproducts and unreacted photo-initiators are able to migrate out of the cured polymers, causing a general hazard.9, 10 Recent studies have shown that benzophenone and its photoproducts are possible carcinogenic to humans (List of IARC (International Agency for Research on Cancer) Group 2B carcinogens).11 Photoinitiators and coinitiators were also found in every single blood serum sample out of 1000 patients,12 proving photoinitiators and their photoproducts are omnipresent contaminants. Nevertheless a major part of the industry uses benzophenone as a photoinitiator due to its low price, availability of many derivatives and its good performance as a Type II photoinitiator. Therefore nonaromatic, nonmigrating, nonmutagenic initiators are of high interest for the coating and packaging industry. A primary aim was to replace the aromatic moiety with aliphatic ones. If schematically one aromatic ring of benzophenone is exchanged with aliphatic structures, it leads to already known phenyl glyoxylates13, 14 or classical acetophenones15 (Fig. 1). By combining these two theoretical concepts, a nonaromatic photoinitiator, the aliphatic α-ketoester was successfully introduced recently.16 α-Ketoesters, ethyl pyruvate for example, are sensitive to UV-light with an absorption maximum at around 330 nm (n-π*). However, the molar extinction coefficient of α-ketoesters is much lower compared to aromatic ring containing photoinitiators, the quantum yield as well as the radical reactivity is much higher.16, 17 α-Ketoesters generate radicals after a triplet-state hydrogen transfer according to a Type II mechanism, rather than Type I α-cleavage [Fig. 2(a)] and the radicals are able to initiate radical polymerization very efficiently as shown in previous studies. Besides acrylates, methacrylates and polyethylene glycol (PEG) diacrylate-based hydrogels also were cured using α-ketoesters as photoinitiators. Ethyl pyruvate was compared to benzophenone/amine in terms of reactivity and achieved nearly double the rate of polymerization with around 200 mmol L−1 s−1 in a diacrylate system.16 Although they still lead to some amount of unreacted photoinitiator leftover in the cured material.6-8 α-Ketoesters themselves and their photoproducts [Fig. 2(b)] are rather harmless to humans.18 This advantage is a significant step forward to biocompatible photoinitiators in packaging and coating industry. Nevertheless the α-ketoester-based photo-initiators and their photoproducts are still able to migrate out of the material. For some products, migration of even nontoxic low molecular compounds have to be avoided. For applications in health care, polymerizable, or macromolecular initiators are the initiator of choice. They are either huge for migrating out of the cured network or are covalently bond into the material during polymerization. α-Ketoglutaric acid (KGA) is a metabolite in the human body, therefore a biocompatible, nonvolatile photoinitiator based on the α-ketoester concept. KGA was tested as an antidote against cyanide poisoning and concentrations of 500 mg kg−1 were applied without any negative immune system response.19 If KGA is released into the body, it is present as α-ketoglutarate, which does not show toxic properties.20 Esters of α-ketoacids, for example ethyl pyruvate and its photoproducts, were tested in terms of cytotoxicity in a previous study. For the highest concentration tested (18 mmol L−1), there was no drop in metabolic activity of mouse fibroblast cells and still above 80% activity for the cells that were irradiated for 10 min by UV-light.16 For the present study, α-ketoglutaric acid was selected for the preparation of polymerizable, macromolecular and polymerizable, macro-molecular derivatives to ensure a low-migration photoinitiator compared to a low molecular weight reference (co)initiator based on the benzophenone/amine system. In detail, the first approach focused on small molecules, equipped with polymerizable end-groups. The concept is based on self-initiating molecules, which are able to covalently bind themselves to the network and copolymerize. The second concept of nonmigratable α-ketoglutaric acid-based photoinitiators focused long polyester chains. After the poly-esterification reaction of KGA with the nontoxic 1,6-hexanediol (LD50 = 3730 mg kg−1),21 the initiators stay in the polyester backbone, while side-branches grow from the KGA building blocks. Therefore the initiator is immobilizing itself due to its molecular weight, even if there is no initiation from each photoinitiator moiety. It is also possible to combine both concepts to achieve immobilization due to the high molecular weight and covalent bonds to the polymer network. As a reference system serves a commercial Type II benzophenone/amine system, majority stays unreacted in the polymer matrix, therefore can migrate out over time. With common industrial standard irradiation times, only a certain amount of amines are able to initiate the polymerization, therefore covalently bind themselves to the network. The benzophenone itself does not initiate. All three concepts plus the reference system were graphically illustrated (Supporting Information Fig. S1). A well-known limitation of polymeric- and covalently bound polymerizable photoinitiators are less photoreactive, due to the decreased diffusion and agility of the formed radicals. Therefore, the reactivity of the photoinitiators as well as the mechanical properties of the resulting polymer networks were investigated. In our experiments the glass transition, the storage modulus at elevated temperatures, tensile strength, and elongation at break were evaluated. α-Ketoglutaric acid (KGA, CAS: 328-50-7, abcr), glutaric acid (GA, CAS: 110-94-1, abcr), para-toluolsulfonic acid (p-TsOH, CAS: 6192-52-5, Sigma Aldrich) and 1,6-hexanediol (HD, CAS: 629-11-8, abcr) were received from the mentioned supplier and purified via recrystallization. Lipase CALB from Candida Antarctica, immobilized on acrylic resin (CAS: 9001-62-1, ≥ 5000 U g−1, Sigma Aldrich), 2-hydroxyethyl methacrylate (HEMA, CAS: 868-77-9, TCI), isophorone diisocyanate (IPDI, CAS: 4098-71-9, TCI), dibutyltin dilaurate (CAS: 77-58-7, Sigma Aldrich), methyl diethanolamine (MDEA, CAS: 105–59-9, Fluka), benzophenone (BP, CAS: 119-61-9, TCI), phenothiazine (CAS: 92-84-2, Sigma Aldrich), butylhydroxytoluol (BHT, CAS: 128-37-0, Sigma Aldrich) and methyl tert-butylether (MTBE, CAS: 1634-04-4, ACROS Organics) were purchased at the mentioned suppliers and used as received. MIRAMER UA5216 (mixture of 60 wt% isobornyl acrylate and 40 wt% of a 30,000 g mol−1 molecular weight polyester urethane diacrylate, Miwon Speciality Chemical) was used as the monomer for all formulations tested. The copolymerizable K2H [Fig. 4(a)] was synthesized similar to the work of Douka et al.,22 Kumar A. and Gross R. A.23 At first, 1 of the α-ketoglutaric of and 1 wt% of Lipase acrylic resin from Candida U were into a equipped with an The reaction was at 60 The reaction was via and thin ethyl = After of reaction time of were applied for min to the due to some formed the was to The of was every After a reaction time of the was with 10 = and was purified by liquid = to A g was used to the and they were via a The with the via were was and the was at the at was into the a to provide for the the of the was by a high at for 10 The K2H was a transparent which was at = = = To the [Fig. a classical according to the was At first all were purified via recrystallization. The para-toluolsulfonic acid was from in and the α-ketoglutaric acid from 1 of the α-ketoglutaric acid and of para-toluolsulfonic acid were into a which was to a 60 were The was to and The reaction was via After a reaction time of the was in of The was a which was in the the was and in of the polyester was in of via a The was a which was in g of and in a molecular weight of g = = = = = To the [Fig. an approach according to the and of for was At first, and isophorone were 1 of isophorone diisocyanate and 1 of with were into a equipped with a After the with an was to the and the was to was via After two of dibutyltin dilaurate were to the After of the not The reaction was to and conversion of the primary The was obtained in a yield of g In a second the was to the g mol−1 to achieve a polymerizable photoinitiator [Fig. to the work of et 1 of the 1 of the two of dibutyltin and 200 phenothiazine as an were into a one with a the was with and equipped with an The was for at and the was at the the was with and the via The was in with a resulting yield of g of = = = = = The experiments were on a system. The were in with butylhydroxytoluol as a concentration of mg for the the were by a to of the polyester the The used and to the molecular weight of the was with a standard from and the was via concentration and of the an and with the was The molecular weight were by To the molecular weight of the different via the were in For the to the in the is to two to the and one in the KGA to the of polymerization and therefore the molecular weight In the case of the two were as reference for molecular weight The in the for the of the molecular are shown in To the reaction of the in the a drop of reaction was the to The resin formulations used for the different was based on the which 60 wt% and 40 wt% of a 30,000 g mol−1 polyester urethane diacrylate (Fig. As a reference Type II photoinitiator system, benzophenone was selected in the concentration of wt% with an amount of coinitiator, to an amount of all α-ketoglutaric acid-based photoinitiators were for the for the 500 of phenothiazine were used as an in all If phenothiazine was introduced into the due to the a decreased amount was to in the 500 for a is a of two there was no in Besides the known for the component a common for similar molecular weight was and to the of = mol−1 or The was using a 1 resulting in g The time the highest is is called The with the rate of polymerization to reactivity of the system. To the time in which of the conversion was achieved the of was to of the the with a specific = = = 40 were manufactured in a after irradiating the liquid with UV-light for the mechanical A based and no applied and the exposure was a of 10 resulting in a irradiation time of the were into with a of one The were into the of the and with a The was 1 at from to 200 The were with sample of the thin of the sample and a of The liquid formulations were cured in an like in the The were into with an of the were into the and the were to the sample in during the The like the yield strength, the applied its maximum the and the elongation at which the maximum elongation of the the sample of the formulations were a glass in and the was to 200 by a was achieved via irradiation with a nm with an with an of at the glass for The were in mg and used for the and They were at the scale and into a containing of methyl tert-butylether for The were and a the were out and after the of the with a they were The was out in around to stay and due to the of which was in the polymer network. the were into an at for to As their weight not any they were the time at the The from the leaching were via a to a into a and by liquid a of = As reference benzophenone and with concentrations of and mg were was The absorption was on different for our only the nm was To a low molecular weight, polymerizable based on to be to an molecule. the initiator to be covalently bound to a growing polymer therefore immobilizing the photoinitiator and it from migrating out of the material. Immobilization even if the initiator is not and therefore not bound to the polymer network. To K2H [Fig. a similar to the work of Douka et al.,22 Kumar A. and Gross R. A.23 was Therefore 1 of α-ketoglutaric of and 1 wt% of acrylic resin from Candida were at 60 in The reaction was via After a reaction time of the was purified by liquid The polymerizable initiator K2H obtained in yield of as a transparent A second approach immobilization of initiator molecules in a cured material is molecular Therefore the photoinitiator be immobilized its and not out of a cured material. The molecular weight was around g which ensure migration for bond photoinitiators. However, compared to commercial high molecular weight initiators were due to initiation the polyester In every second building of the polyester is able to initiate polymerization. By using a molar of the molecular weight was via and in g mol−1 by of KGA and 1,6-hexanediol the g only of the molecular weight was due to the of the poly-esterification The reaction was after around in to and to be avoided. To the [Fig. a according to the was Therefore of the α-ketoglutaric of a amount of para-toluolsulfonic acid in were to and the formed was via After a reaction time of the was and in as The polyester was used as material for the with The methacrylate on both of the polyester the polymer to be covalently into the polymer network during Although the polyester is from due to its molecular weight, the of the achieve even in leaching compared to without methacrylate To covalently bind the initiator into the cured network via polymerizable to be to the polyester All previous polyester were to have which could be in high via of an Therefore was with the primary of isophorone The was out according to the and of for The resulting can be to a To the [Fig. 1 of isophorone diisocyanate was with 1 of 2-hydroxyethyl methacrylate and the reaction was via and dilaurate was to conversion, therefore was used without for the step of The of the polymerizable initiator [Fig. was based on the work of et by of the of to the of a urethane To the 1 of the polyester and of the were in using dibutyltin dilaurate as a and was selected to conversion of the of the the polymer was in resulting in a yield of of as To an of the molecular weight of each was in combination with the of g is in good with the g weight obtained for are increased by around g mol−1 compared to which is the of the two g to the A second to the molecular weight of the was to the obtained by were and the obtained with the in the For the the to the was and to a of one from the and one from the KGA were The obtained of the the number of and KGA molecules the polyester (Supporting Information Fig. In case of in there were g and KGA g molecules to a By the of the and the g a of g mol−1 was The molecular weight well with the molecular weight via the for the to on two of the and each to the resulting molecular weight is g The for was (Supporting Information Fig. The decreased as the reaction over time and the of new and were due to the formed urethane bonds (Supporting Information Fig. All formulations were based on the UA5216 based on a polyester urethane diacrylate of a molecular weight of 30,000 g mol−1 and as was used as a reference photoinitiator in the concentration of wt% with an amount of as The concentrations are selected rather not in the coating industry increased photoinitiator of the thin the irradiation to the weight percentage of an amount of all α-ketoglutaric acid-based formulations were to ensure a (Supporting Information For the macromolecular photoinitiator, the molar was based on the of the amount to wt% of to wt% of wt% of and wt% of All α-ketoester based photoinitiators were used without coinitiator in the experiments [Fig. To the reactivity of the synthesized α-ketoglutaric acid-based were the reactivity of the generated radicals. For the of the formulations based on wt% were used as The maximum of benzophenone and the α-ketoesters is very similar 330 therefore the irradiation can be used. The of the used photoinitiators can be found in Information and In terms of reactivity in the rate of polymerization [Fig. the commercial system is of the α-ketoglutaric acid based macromolecular and polymerizable K2H photoinitiators. Due to the of K2H to copolymerizable with the the and reactivity of the initiator As the was even by using photoinitiators like the The radicals generated at the long polymer have lower diffusion and therefore show decreased To of the conversion [Fig. the new and the polymerizable K2H are only than the low molecular reference initiator The [Fig. of the α-ketoglutaric acid based photoinitiators is well above the commercial initiator system It was the lower of the initiator system benzophenone/amine was due to its on diffusion of the as and the α-Ketoesters not a coinitiator to initiate as hydrogen can be from itself or molecules Therefore α-ketoester-based initiators react in terms of rate of polymerization, increased conversion are compared to the reference system can be found in Information To the mechanical properties of the for glass and the storage modulus over a mechanical was The for the were on of the formulations mentioned in the previous The glass is as the maximum of from a other it is to the in the resulting polymer achieved by a photoinitiator. If the sample during the at a certain a in the storage modulus like for the system at around can be (Supporting Information Fig. as reference initiator in a material with a of [Fig. The rather small initiator K2H the due to the increased achieved by two methacrylate which is a polyester with some radical its decreased the glass by compared to and therefore as a in the material. With the of methacrylate in the the glass was to due to compared to the storage modulus [Fig. of the at elevated a can be according to their The modulus was achieved by the reference initiator system with and to by or into the resulting in above 1 were achieved by the which is a small with possible to two To the tensile and elongation at tensile were with all sample [Fig. The for tensile were out of the formulations in the The benzophenone/amine photoinitiator system 10 Information Fig. of maximum tensile and an of nearly (Fig. Due to the high and increased of the K2H achieved the highest in applied with This is an of tensile compared to by a of while elongation at break still stays above the maximum of the macromolecular photoinitiators, a is for due to its initiation the polymer the tensile even to 17 due to its polymerizable methacrylate and network. the for the macromolecular molecules, elongation can be due to the covalent bonds to the matrix and an step for the polymerizable initiator material migration out of cured polymer networks was a major To the amount of not covalently bound initiator molecules and in a cured leaching were Therefore of the by their during leaching was (Supporting Information All used for leaching were based on the formulations The experiments [Fig. similar for and as initiator with a of for As the small copolymerizable photoinitiator K2H achieved less of due to the network. After the was and the were the on was by with a of around [Fig. All α-ketoglutaric acid based achieved leaching properties with a maximum of less than The or high molecular weight compounds are introduced into a the less was Therefore the polymerizable achieved the during tensile by the and the polymerizable To and the which out of the polymer a was At first the of the formulations were in known concentrations to the times and of each component (Supporting Information Fig. and to min can be to The coinitiator no significant absorption at the selected of The times and of the were compared to the leaching of the (Supporting Information Therefore it was possible to which and amount out of a cured For the of the an of the leaching was into a and at the The reference material cured by benzophenone [Fig. a major amount of initiator = and isobornyl acrylate = The polymerizable K2H and both macromolecular photoinitiators [Fig. out some unreacted = To the amount of leaching a (Supporting Information Fig. the absorption and the concentration of the was by standard of benzophenone and isobornyl acrylate The resulting was used to the concentration of a component by its absorption The sample containing nearly of its photoinitiator and of the used The leaching was similar with for the and the which is nearly double the amount of acrylate compared to and K2H (Supporting Information In the around of the leachables were for the benzophenone/amine sample that the part of of the of K2H was found in the For the macromolecular initiators and above of the leachables were therefore nearly no were rather in the network (Supporting Information As no leaching of photoinitiators can be with all new A variety of α-ketoglutaric acid-based were successfully They can be into three polymerizable initiators and The synthesized photoinitiators are to show less compared to a classical Type II photoinitiator based on benzophenone/amine as In an industrial the rate of polymerization and the were for the reference system, the α-ketoesters The lower reactivity of the copolymerizable and systems were due to the lower radical as an industrial scale monomer with good mechanical were manufactured for mechanical all α-ketoester-based initiators an in glass and storage modulus at elevated compared to the benzophenone/amine system. is the of the polymerizable with an of storage modulus by a of and a glass above was also by the different α-ketoesters, due to the initiation the at break still at a The properties were obtained in containing K2H and as photoinitiators. The leaching by the photoinitiators. to the benzophenone/amine system, which a of around and nearly of the photoinitiator amount as well as of the used monomer The α-ketoester a of maximum and of the in case of the K2H photoinitiator. were no photoinitiator leachables for all α-ketoester Information The is not for the or of any by the than be to the for the

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