Hydrophilic Polymeric Acylphospine Oxide Photoinitiators

Biomacromolecules 2001, 2, 1271-1278

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Hydrophilic Polymeric Acylphospine Oxide Photoinitiators/ Crosslinkers for in Vivo Blue-Light Photopolymerization Jacqueline H. de Groot,*,† Keith Dillingham,† Henk Deuring,† Henk J. Haitjema,† Folkert J. van Beijma,† Kenn Hodd,‡ and Sverker Norrby† Pharmacia Van Swietenlaan 5, 9728 NX Groningen, The Netherlands, and Polykendra Ltd., Wrexham LL12 9EW, U.K. Received July 10, 2001; Revised Manuscript Received September 11, 2001

Three vinyl-functionalized phosphine oxide photoinitiating monomers have been synthesized: 4-vinylbenzoyldiphenylphosphine oxide (VBPO), 2,6-dimethyl-4-vinylbenzoyldiphenylphosphine oxide (DMVBPO), and 2,4,6-trimethylbenzoylphenyl-4-vinylphenylphosphine oxide (TMBVPO). VBPO was copolymerized with vinylpyrrolidone or vinyl acetate (PPI-1a) and dimethylacrylamide (PPI-1b). DMVBPO and TMBVPO were both copolymerized with dimethylacrylamide (PPI-2 and PPI-3, respectively). The choice of vinylphosphine oxide and comonomer(s) had a significant influence on the properties of the resulting PPI. PPI-1a was not stable in solution in 2-hydroxyethyl methacrylate (HEMA), whereas the VBPOdimethylacrylamide (DMA) copolymer (PPI-1b) was stable in HEMA but not stable in aqueous solutions. PPI-2 was both soluble and stable in water up to 22 months. PPI-1a was as effective as trimethylbenzoyldiphenylphosphine oxide (TPO, BASF Lucirin). PPI-2 was more effective in the polymerization of HEMA/ water mixtures than PPI-3. PPI-2 and PPI-3 acted as self-cross-linking species, resulting in the formation of hydrogels; PPI 3 was more effective in this. PPI-2 was very effective in forming hydrogels based on poly(ethylene glycol) diacrylate. Introduction In vivo polymerization of injectable prepolymer liquids is now widely used for biomedical applications such as bone cements and tooth fillings because it provides the possibility of forming polymers in complex shapes. Implantation can be performed through small holes and is, therefore, less invasive than conventional surgical techniques. These advantages have motivated researchers to investigate this technique for other applications such as postoperative prevention of tissue adhesion,1 tissue adhesives,2 homeostatic glue,3 tissue engineering,4,5 and intraocular lenses.6-9 Both photopolymerization and thermal polymerization have been reported. Thermal polymerization has certain disadvantages. In some cases, elevated temperatures are needed, which can be damaging to tissue. In other cases, the systems cure at room or body temperature, which narrows the process window or extends the setting time unacceptably. A system that sets quickly on command is preferred, and photopolymerization provides this opportunity. For in vivo applications, systems that can be cured under the influence of visible light are favorable, as UV light is damaging to living tissue. It is, therefore, of interest to develop visible light photoinitiators for biomedical applications. During photopolymerization, a substantial percentage of unreacted molecules remains. Together with less reactive * Corresponding author: Jacqueline H. de Groot. E-mail: [email protected]. Tel.: ++31 50 5296643. Fax: ++31 50 5276824. † Pharmacia Van Swietenlaan 5. ‡ Polykendra Ltd.

photoinitiator fragments, they will be able to migrate out of the material. Because the substances are considered toxic, this migration should be prevented in biomedical applications. Therefore, it is desirable to incorporate the photoinitiator into a polymer. There are two types of photoinitiators. Type I photoinitiators fall apart into two radicals. Type II photoinitiators require a co-initiator/accelerator, usually a tertiary amine, to become reactive.10 To overcome the occurrence of migration in the case of type I systems, one must incorporate the photoinitiator into a polmyer, whereas in the case of type II systems, one must incorporate the sensitizer and co-initiator/accelerator into the either same polymer or different polymers. It is, therefore, more straightforward to use polymeric type I photoinitiators. The photoinitiators used in this study are phosphine oxides. They can be used for wavelengths up to 420 nm and have been shown to be highly reactive toward acrylates, styrene, and other vinyl monomers.11 Unlike other type I photoinitiators, the reactivities of the radicals used in this study do not differ much. The phosphinoyl radical proved to be twice as effective as the benzoyl radical. An advantage of these photoinitiators is that they are able to photopolymerize thick layers.12 Phenyl-substituted phosphine oxides were chosen for this study because it has been shown that, compared to other substituents, their absorption increases, and their spectrum shifts toward the blue to 420 nm.13 This enables blue-light photopolymerization. Angiolini et al. linked acyl phosphine oxides to polymers successfully.14,15 Polymeric photoinitiators were prepared by

10.1021/bm015584r CCC: $20.00 © 2001 American Chemical Society Published on Web 11/06/2001

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reacting homopolymers or copolymers of 4-acryloyl benzoic acid or 4-acryloyl-2,6-dimethyl benzoic acid with thionyl chloride followed by methoxydiphenylphosphine. By linking the acylphosphine oxide at the benzoyl side to the polymer, the more reactive phosphinoyl radical can initiate the polymerization. The polymeric photoinitiators showed excellent performance. However, obtaining high conversion of the benzoyl chloride groups attached to the polymer was difficult because of their reduced reactivity. A way to overcome this problem is to first synthesize an acylphosphine oxide monomer and then copolymerize it with other monomers to form a polymeric acylphosphine oxide photoinitiator.16 This approach was adopted for the synthesis of 4-vinylbenzoyldiphenylphosphine oxide (VBPO), 2,6dimethyl-3-vinylbenzoyldiphenylphosphine oxide (DMVBPO), and 2,4,6-trimethylbenzoylphenyl-4-vinylphenylphosphine oxide (TMBVPO). These monomers were copolymerized with other monomers including vinyl acetate (VAc), N-vinylpyrrolidone (NVP), and dimethylacrylamide (DMA) to give water-soluble polymeric photoinitiators. The polymeric photoinitiators were tested for their solubility and stability. Their efficiency in polymerizing under the influence of blue light was tested and compared to that of the commercially available low-molecular-weight trimethylbenzoyldiphenylphosphine oxide (TPO, BASF Lucirin). Moreover, hydrogels were made with PPI-2 and PPI-3, which are copolymers of DMVBPO and TMBVPO, respectively, with DMA. In addition hydrogels based on poly(ethylene glycol) diacrylate were made with PPI-2. Experimental Section Materials. All chemicals were purchased at SigmaAldrich. Monomers were distilled before use. AIBN was recrystallized twice from methanol. Methoxydiphenylphosphine was prepared as previously reported,17 starting from chlorodiphenylphosphine (Aldrich) and methanol in the presence of N,N-diethylaniline, distilled under high vacuum (bp ) 114-115 °C/0.1 mmHg), and stored under dry nitrogen. Trimethylbenzoyldiphenylphosphine oxide (TPO), Lucirin, was obtained from BASF. Photoinitiator Precursors. The synthetic routes are shown in Schemes 1-3. 4-Vinyl Benzoyl Chloride (I-2). To 11.9 g (0.101 mol) of thionyl chloride (cooled to ∼3 °C) was added 3.55 g (24.0 mmol) of 4-vinyl benzoic acid in portions. The solution was stirred for 4 h while the temperature was kept below 10 °C. Then, the orange solution was stirred for 1 h at 40 °C. The solution was heated to 135 °C, and after the thionyl chloride was distilled off, 4-vinyl benzoyl chloride was distilled as a colorless liquid. 1H NMR (CDCl ): δ 5.5 (1H, d, CH), 5.9 (1H, d, CH), 3 6.7 (1H, dd, CH), 7.5 (2H, d, ar), 8.1(2H, d, ar). 4-Bromo-2,6-xylidine (II-2). To a solution of 60.0 g (0.5 mol) of xylidine in 60 mL of acetic acid was added a solution of 25.7 mL (0.5 mol) of bromine in 70 mL of acetic acid over the course of 45 min. After 1 h of stirring at room temperature, the mixture was filtered. The 4-bromo-2,6-

de Groot et al.

xylidine HBr salt obtained was suspended in 500 mL of water. The mixture was basified to pH 8-9 with 25% NH4OH (dropwise addition). The product was filtered and dried to yield 94.0 g (95%) of 4-bromo-2,6-xylidine. 1H NMR (CDCl ): δ 2.1 (6H, s, CH ), 3.5 (2H, r s, NH ), 3 3 2 7.0 (2H, s, ar). 4-Bromo-2,6-xylonitrile (II-3). A suspension of 100 g (0.5 mol) of 4-bromo-2,6-xylidine in 500 mL of 2 N HCl was cooled to 0 °C. Next, a solution of 43.0 g (0.63 mol) of sodium nitrite in 150 mL of water was added dropwise over 30 min. After being stirred for 1 h at 4 °C, the solution was neutralized to pH 7-8 by the portionwise addition of sodium carbonate. The resulting diazo solution was added in 10 equal portions, over 1 h, to a well-stirred CuCN solution at 60 °C. The CuCN solution was prepared from 61 g of Cu(I)Cl in 400 mL of water and 75 g of NaCN in 450 mL of water. After the addition was completed, the reaction mixture was stirred for 2 h at 100 °C. Next, 800 mL of toluene was added, and the mixture was cooled to room temperature. After filtration over Celite, the mixture was separated, and the water layer was extracted with toluene. The combined toluene layers were washed with water, dried over sodium sulfate, filtered, and evaporated. The residue was distilled, bulb-tobulb, at 110 °C and 0.01 mbar. The distillate, which solidified upon standing, was stirred with 50 mL of ethanol at 5 °C. The product was filtered and dried to yield 50.9 g (48%) of the white solid 4-bromo-2,6-xylonitrile. 1H NMR (CDCl ): δ 2.45 (6H, s, CH ), 7.3 (2H, s, ar). 3 3 4-Bromo-2,6-xylic Acid 4 (II-4). A mixture of 8 g (0.04 mol) of 4-bromo-2,6-xylonitrile in 11 mL of H2O and 14 mL of H2SO4 was heated for 2 h at 150 °C. The mixture was cooled, water (50 mL) was added, and the product was extracted with ether (3 × 25 mL). The ether layer was washed with water (1 × 50 mL), dried (sodium sulfate), filtered, and evaporated to give 7.7 g of crude 4-bromo-2,6xylic acid. The crude product was recrystallized from 80 mL of chloroform to yield 5.5 g (64%) of 4-bromo-2,6-xylic acid as a white solid. 1H NMR (CDCl ): δ 2.4 (6H, s, CH ), 7.2 (2H, s, ar). 3 3 4-Formyl-2,6-xylic Acid (II-5). A solution of 32.6 g (0.14 mol) of 4-bromo-2,6-xylic acid in 325 mL of THF was cooled to -80 °C. Next, 118 mL of 2.5 n-butyllithium was added dropwise over 20 min. After being stirred for 15 min at -70 °C, the mixture was cooled to -80 °C, and 33 mL (0.33 mol) of DMF was added dropwise in 5 min. The reaction was stirred for 30 min, during which the temperature was allowed to reach -20 °C. Next, 250 mL of water was added, and the THF was evaporated. The basic water layer was extracted with ether (2 × 100 mL). The water layer was acidified to pH 4-5 and then by dropwise addition to pH 1, at which point 4-formyl-2,6-xylic acid crystallized. The product was filtered and dried to yield 15 g (60%) of 4-formyl-2,6-xylic acid as a white solid. 1H NMR (CDCl ): δ 2.4 (6H, s, CH ), 7.2 (2H, s, ar), 9.9 3 3 (1H, s, CHO). 4-Vinyl-2,6-xylic Acid (II-6). To a suspension of 30.2 g (0.085 mol) of methyltriphenylphosphonium bromide and 250 mg of 18-crown-6 in 150 mL of THF was added 18.75 g (0.17 mol) of KOtBu in portions. A solution of 12.6 g

Photoinitiators for in Vivo Blue-Light Photopolymerization

(0.071 mol) of 4-formyl-2,6-xylic acid in 75 mL of THF was added dropwise. The temperature was kept at 20-25 °C during the additions. The reaction mixture was stirred for 18 h at room temperature. The THF was evaporated, water (150 mL) was added, and the mixture was extracted with ether (1 × 100 mL). The water layer was acidified to pH 1 with 2 N HCl and extracted with ether (2 × 150 mL). The ether layer was washed with water, dried (sodium sulfate), filtered, and evaporated. The solid residue was recrystallized from hexane/ethyl acetate (6/1) to yield 8 g (64%) of 4-vinyl-2,6-xylic acid as a white solid, and 3 g (25%) was obtained from the mother liquor. 1H NMR (CDCl ): δ 2.4 (6H, s, CH ), 5.3 (1H, d, CH), 3 3 5.7(1H, d, CH), 6.6 (1H, dd, CH), 7.1 (2H, s, ar), 11.0 (1H, br s, OH). 4-Vinyl-2,6-xylic Acid Chloride (II-7). To 11.9 g (0.101 mol) of thionyl chloride (cooled to ∼3 °C) was added 4.23 g (24.0 mmol) of vinyl-2,6-xylic acid in portions. The solution was stirred for 4 h while the temperature was kept below 10 °C. Then, the orange solution was stirred for 1 h at 40 °C. The solution was heated to 135 °C, and after removal of the thionyl chloride, 4-vinyl-2,6-xylic acid chloride was distilled as a colorless liquid. 1H NMR (CDCl ): δ 2.4 (6H, s, CH ), 5.3 (1H, d, CH), 3 3 5.7(1H, d, CH), 6.6 (1H, dd, CH), 7.1 (2H, s, ar). Chlorodiethylamino Phenylphosphine (III-2). A solution of 100 mL (0.73 mol) of dichlorophenylphosphine in 800 mL of ether was cooled to 0 °C. Diethylamine (153 mL, 1.46 mol) was added dropwise over 30 min at 0-10 °C. The reaction mixture was refluxed for 2 h. The mixture was cooled to room temperature and filtered. The solvent was evaporated to give 153 g (97%) of chlorodiethylaminophenylphosphine as an oil, which was sufficiently pure for use in the next step. Diethylamino-p-styrylphenylphospine (III-3). To 9.7 g (0.4 mol) of magnesium turnings was added dropwise a solution of 3 mL (0.04 mol) of ethylbromide in 5 mL of THF. A solution of 27.6 g (0.2 mol) of p-chlorostyrene in 75 mL of THF was added, and the reaction mixture was refluxed for 15 min. The mixture was cooled to room temperature and added dropwise over the course of 30 min to a solution of 36.4 g (0.17 mol) of chlorodiethylaminophenylphosphine at 5-10 °C. The reaction mixture was stirred for 30 min at room temperature, THF was evaporated, 200 mL of cyclohexane was added, and the mixture was filtered through Celite. The solvent was evaporated to give 28 g (50%) of diethylamino-p-styrylphenylphosphine as an oil, which was used in the next step without further purification. Methoxy-p-styrylphenylphosphine (III-4). To 28 g (0.1 mol) of diethylamino-p-styrylphenylphosphine was added 150 mL of methanol. The reaction mixture was stirred for 18 h at room temperature under nitrogen. The mixture was filtered, and the methanol evaporated. The residue was purified twice by column chromomatography over neutral aluminum oxide. The volatile contaminants were removed at 50 °C, 0.002 mbar, to give 16 g (66%) of methoxy-pstyrylphenylphosphine as a pale yellow oil. 1H NMR (DMSO-d ): δ 3.6 (3H, d, CH ), 5.3 (1H, d, 6 3 CH), 5.9 (1H, d, CH), 6.7 (1H, dd, CH), 7.4 (9H, m, ar).

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Synthesis of Photoinitator Monomers and Their Copolymerization. Synthesis of Copoly(VBPO-NVP-VAc) (Polymeric Photoinitiator 1a, PPI-1a). A detailed description of the synthesis of VBPO and copolymerization with NVP and VAc is described elsewhere.15 Methoxydiphenylphosphine and 4-vinylbenzoyl chloride were reacted in toluene at 65 °C. After the reaction, vinyl acetate and N-vinylpyrrolidone were added, along with AIBN. The copolymerization was performed at 65 °C. The polymer was purrified by precipitation, with a yield of 72%. Synthesis of Copoly(VBPO-DMA) (PPI-1b). A detailed description of the synthesis of VBPO and copolymerization with DMA is described elsewhere.15 The yield was 60%. Synthesis of Copoly(DMVBPO-DMA) (PPI-2). The same procedure as cited above was followed with 0.947 g (4.34 mmol) of methoxydiphenylphosphine and 0.834 g (4.30 mmol) of 4-vinyl-2,6-dimethyl benzoyl chloride at the start. The resulting DMVBPO was copolymerized, without further purification, with 10.421 g (0.105 mol) of DMA using 120 mg (0.73 mmol) of AIBN. The yield was 54%. The friable pale yellow polymer contained 0.73 wt % P. Synthesis of Copoly(TMBVPO-DMA) (PPI-3). The same procedure as cited above was followed with 1.061 g (5.70 mmol) of 2,4,6-trimethyl benzoyl chloride and 0.800 g (3.31 mmol) of methoxy-p-styrylphenylphosphine as starting materials. The resulting TMBVPO was copolymerized, without further purification, with 10.241 g (0.103 mol) of DMA and 120 mg (0.73 mmol) of AIBN. The yield was 86%. The polymer contained 0.87 wt % P. Methods. Determination of Photoinitiator Contents in the Polymers. The percentage of photoinitiator was determined by a calculation comparing the signal of the phenyl groups (6.6-8.4 ppm) relative to the signal of rest of the polymer (1-5 ppm) in the 1H NMR spectra of the polymers (obtained using a Varian Unity 300 spectrometer). A correction was made for the protons of the photoinitiator that fall in the range of 1-5 ppm, which are the backbone protons and the protons of the two methyl groups in the case of PPI-2 and PPI-3. The amount of photoinitiator was also determined by elemental analysis. Photocalorimetric Experiments. Photocalorimetric studies were performed using a DSC 2920 modulated DSC (TA Intruments) in combination with a blue-light dental gun (Heliolux DLX, Vivadent). 2-Hydroxyethyl methacrylate (HEMA, optical-grade, Polyscience), photonitiator, and, in some cases, water were mixed in subdued light. A ∼10 mg sample of the mixture was pipetted into an open DSC aluminum sample pan. The sample pan, covered with a cover-slip of thin glass, was placed in the sample position of the head of the DSC. The temperature of the head was allowed to stabilize under N2 at 37 °C (or in some cases 23 °C), and the sample was irradiated with blue light at 8 mW/ cm2 (determined with a radiometer, International Light). The area of the polymerization exotherm was determined by conventional computation, and the amount of heat per gram of the monomer was calculated (J/g). From this value, the percentage conversion of monomer to polymer was

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Table 1. Characteristics of Polymeric Photoinitiators Synthesized

PIa PPI-1ae PPI-1bg PPI-2h PPI-3i TPOj

PI in polymer (mol %)

PI in feed (mol %)

NMR

EAb

mequiv/gc

solubility in water

Mn (×103)

Mw (×103)

Dd

3.5 6.0 4.1 3.1 nak

2.3 5.4 2.5 3.1 na

2.4 5.3 2.6 3.0 na

0.21 0.52 0.24 0.27 2.88

+ + + -

32 ndf 5.6 9 na

103 nd 24 35 na

3.2 nd 4.3 3.8 na

a Photoinitiator. b Elemental analysis. c Milliequivalents of phosphine oxide per gram of photoinitiator. d Polydispersity. e Copolymer of vinylbenzoyldiphenylphosphine oxide, vinyl acetate, and N-vinylpyrrolidone. f Not determined. g Copolymer of vinylbenzoyldiphenylphosphine oxide and dimethylacrylamide. h Copolymer of vinyldimethylbenzoyldiphenylphosphine oxide and dimethylacrylamide. i Copolymer of trimethylbenzoylvinyldiphenylphosphine oxide and dimethylacrylamide. j Trimethylbenzoyldiphenylphosphine oxide (Lucirin). k Not applicable.

Scheme 1. Synthetic Route for Polymeric Photoinitiators 1a and 1b

Figure 1. Exotherms of polymerization of HEMA/PPI-1a (90/10 wt %) initiated with blue light (8 mW/cm2) after different storage times (at room temperature): - - -, 0.3 h; - - -, 0.9 h; - ‚ - ‚ -, 1.6 h; - ‚‚ - ‚‚ -, 2.3 h.

calculated using a literature value for the latent heat of polymerization of HEMA, ∆Hp.18 Absorption. The UV/vis absorption spectra of the polymeric photoinitiators were recorded on a Hewlett-Packard 8452A computerized spectrophotometer. Hydrogels. PPI-2 (0.025 g) and poly(ethylene glycol) diacrylate PEGDA (0.475 g) were dissolved in 5.0 g of saline in the dark. The solution was transferred into a syringe with an 18G needle and injected into a mold comprising two microscopic glass plates separated by a Teflon spacer (diameter of 1 cm, thickness of 4 mm). The molds were illuminated with blue light from one of two light sources, either a dental gun (Heliolux DLX, Vivadent) or an industrial blue-light source (EFOS).

Figure 2. Exotherms of polymerization of HEMA/TPO (99/1 wt %) initiated with blue light (8 mW/cm2) 0.3 and 3.0 h after preparation of formulation at 37 °C. Curves virtually coincide.

Results and Discussion Acylphosphines were prepared in almost quantitative yield by the Michaelis-Arbuzov14 reaction between alkoxyphosphines and acyl chlorides. The first photoinitiator precursor, VBPO, was made by the reaction of 4-vinylbenzoyl chloride and methoxydiphenylphosphine, as described in Scheme 1. The pale yellow polymer, polymeric photoinitiator 1a (PPI1a), was easily isolated. The amount of the phosphine moiety in it was determined by 1H NMR spectroscopy and elemental analysis and is reported in Table 1. The results of the NMR measurements and elemental analysis are in good agreement. Photopolymerization of HEMA/PPI-1a mixtures were carried out using DSC to determine the efficiencies of the photoinitiators. This technique measures the rate of heat

produced, as well as the total amount of heat produced, from radical polymerization, which is related to the conversion of HEMA to polyHEMA.17 In Figure 1, the heat flow exotherms of blue-light HEMA polymerizations with PPI-1a at different storage times of the HEMA/PPI-1a solution are shown. To measure the polymerization heat, a second scan was performed to determine the baseline, which corresponds to nonpolymerizing material. For comparison, HEMA was also polymerized with the low-molecular-weight commercially available photoinitiator trimethylbenzoyldiphenylphosphine oxide (TPO, BASF Lucirin), which is shown in Figure 2. In Table 2, the corresponding heats of polymerization are presented.



Table 2. Polymerization Heats of HEMA Initiated with PPI-1a and b and TPO under the Influence of Blue Light at Different Times after Preparation of the Formulation formulation (wt %)

mequiv/ga

timeb (h)

90 HEMA/10 PPI-1ae 90 HEMA/10 PPI-1a 90 HEMA/10 PPI-1a 90 HEMA/10 PPI-1a 99 HEMA/1 TPOf 99 HEMA/1 TPO 90 HEMA/10 PPI-1bg 90 HEMA/10 PPI-1b

2.1 2.1 2.1 2.1 2.9 2.9 5.2 5.2

0.3 0.9 1.6 2.3 0.3 3.0 0.2 120

∆Hc × 102 conversiond (J/g) (%) 2.4 2.4 2.3 2.1 3.6 3.6 3.6 3.6

55 55 53 48 82 82 82 82

a

Milliequivalents of phosphine oxide per gram of photoinitiator. b Time stored in the dark at 23 °C. c Heat of polymerization per gram of HEMA. d Calculated as a percentage of 4.4 × 102 J/g.17 e Copolymer of vinylbenzoyldiphenylphosphine oxide, vinyl acetate, and N-vinylpyrrolidone. f Trimethylbenzoyldiphenylphosphine oxide (Lucirin). g Copolymer of vinylbenzoyldiphenylphosphine oxide and dimethylacrylamide.

Figure 4. Exotherms of HEMA/water mixture with PPI-1b (50 HEMA/ 45 H2O/5 PPI-1b) initiated with blue light (8 mW/cm2) after different storage times (at room temperature): - - -, 0.2 h; - - -, 0.9 h; - ‚ ‚ -, 19 h. Table 3. Polymerization Heats of HEMA/Water Mixtures Initiated by PPI-1b and Blue Light (8 mW/cm2) at Different Times after Preparation of the Formulation formulation timeb ∆H × 102 conversiond (wt %)

mequiv/ga

(h)

(J/g)c

(%)

50 HEMA/45 H2O/5 PPI-1be 50 HEMA/45 H2O/5 PPI-1b 50 HEMA/45 H2O/5 PPI-1b

5.2 5.2 5.2

0.2 0.9 19

4.8 4.5 1.1

109 102 25

a Milliequivalents of phosphine oxide per gram of photoinitiator. b Storage time at 23 °C. c Heat of polymerization per gram of HEMA. d Calculated as a percentage of 4.4 × 102 J/g.17 e Copolymer of vinylbenzoyldiphenylphosphine oxide and dimethylacrylamide.

Figure 3. Heat flow exotherms of polymerization HEMA/PPI-1b (90/ 10 wt %) initiated with blue light (8 mW/cm2) 0.2 and 120 h after preparation of the formulation at 37 °C. The curves vitually coincide.

The heats of polymerization of HEMA with PPI-1a and TPO are 240 and 360 J/g, respectively, and the polymeric photoininitiator appeared less effective than TPO. HEMA polymerized in 5 min with PPI-1a and in 1.5 min with TPO. The shape of the photopolymerization exotherm curve changes, the polymerization time increases, and the heat of polymerization decreases with increasing time of storage of the PPI-1a/HEMA solutions. These are indications that the polymeric photoinitiator is not stable in HEMA, unlike TPO. It is known that acylphosphine oxides lack stability. They are prone to undergo solvolytic cleavage of the carbonphosphorus bond in the presence of nucleophilic compounds, such as water, alcohols, and amines.19 It has been shown that the solvolytic stability of acylphosphine oxides is greatly enhanced by the introduction of bulky substituents in positions where the carbonyl group is shielded from nucleophilic attack. An introduction of two methyl substituents in the ortho positions of the benzoyl moiety, in the case of TPO, improves the solvolytic stability so that it is sufficient for most practical applications.12 VBPO was also copolymerized with dimethylacrylamide (DMA) to obtain PPI-1b. The characteristics of this photoinitiator are shown in Table 1. In Figure 3, the heat exotherm of HEMA polymerization with PPI-1b is shown. The curve

shape, polymerization time, and heat of polymerization are identical to those of HEMA polymerization with TPO. The comonomer apparently has an influence on the stability of the photoinitiator. For applications where the reactive component is a fluid, such as low-molecular-weight poly(ethylene glycol) acrylates, diacrylates, or acrylate-modified silicones, this photoinitiator can be used. For applications where the reactive component is a solid, for instance, acrylate-modified polymers with higher molecular weights, water is needed in the formulation to allow injectability. In these cases, the stability of the photoinitiator in water becomes crucial. Therefore, the stability of PPI-1b in water was tested. In Figure 4, the heat exotherms of HEMA polymerized in water are shown as a function of storage time. In Table 3, the corresponding heats of polymerization are shown. It can be concluded that PPI-1b is not stable in the presence of water. The polymerization heat decreases dramatically with time. The presence of water did not have an effect on the polymerization time. Notable is the high conversion of HEMA in this case. The polymerization enthalpies and conversions were larger than those found in the literature.17 We do not have an explanation for this. To increase the stability of the PPI in water, a polymeric TPO analogue (PPI-2) was made by copolymerizing vinyldimethylbenzoyldiphenylphosphine oxide with dimethylacrylamide. The preparation of 4-vinyl2,6-dimethylbenzoyldiphenylphosphine oxide is described in Scheme 2. The characteristics of PPI-2 are described in Table 1. This polymer is also water-soluble, and to test the stability of this polymeric photoinitiator in water, it was used for the polymerization of HEMA/water mixtures after storage in aqueous solution, in the dark, for between 13 days and 22

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Table 4. Polymerization Exotherms of HEMA/Water Mixtures Initiated by PPI-2 and Blue Light (8 mW/cm2) after Storage of the Formulation for Increasing Periods in the Dark at 23 °C

d

formulation (wt %)

mequiv/ga

timeb

∆Hc × 102 (J/g)

conversiond (%)

polymerization time (min)

50 HEMA/45 H2O/5 PPI-2e 50 HEMA/45 H2O/5 PPI-2 50 HEMA/45 H2O/5 PPI-2 50 HEMA/45 H2O/5 PPI-2 50 HEMA/45 H2O/5 PPI-2 50 HEMA/45 H2O/5 PPI-2 50 HEMA/45 H2O/5 PPI-2

1.2 1.2 1.2 1.2 1.2 1.2 1.2

13 d 2m 3m 5m 8m 10 m 22 m

4.9 4.9 4.8 4.9 5.0 5.1 4.9

112 112 110 112 114 116 112

5 5 5 5 5 5 5

a Milliequivalents of phosphine oxide per gram of photoinitiator. b Storage time; d ) days, m ) months. c Heat of polymerization per gram of HEMA. Calculated as a percentage of 4.4 × 102 J/g.17 e Copolymer of vinyldimethylbenzoyldiphenylphosphine oxide and dimethylacrylamide.

Scheme 2. Synthetic Route for Polymeric Photoinitiator 2 (PPI-2)

Figure 5. Absorption spectrum of 3 wt % PPI-2 in chloroform after different times of illumination with blue light: s, 0 s; - - -, 80 s; - ‚ ‚ -, 160 s; - ‚‚ - ‚‚ -, 460 s.

months at room temperature. From Table 4, it can be seen that, even after storage in water for up to 22 months, the polymerization characteristics of HEMA when initiated with PPI-2, i.e., the polymerization exotherm and the rate of polymerization, did not change. PPI-2 was found to be stable over this period, which enables its use for many applications, particularly the target application of an injectable formulation. Additionally, its higher stability in HEMA gave an increased conversion to polyHEMA than was the case for PPI-1a or PPI-1b. In Figure 5, the absorption spectrum of PPI-2 in chloroform after illumination with blue light is shown. The absorption in blue and near-UV light decreases with illumination. Thus, the chromophoric group of the photoinitiator responsible for long-wavelength absorption reduces during the photochemcial reaction of the photoinitiator. This increases the efficiency of the photochemical reaction because the fragments do not compete with the light absorption by the photoinitiator. A decreasing optical density permits a continuously deeper penetration of incident light. This is the reason, in contrast to most other photoinitiators,

that the curing of thick layers possible. This phenomenon is called photobleaching. Upon illumination, the polymer becomes yellower, which is shown by the increasing absorption at 400-500 nm, although this coloration decreases with time. PPI-2 initiates the polymerization of HEMA effectively under blue light, even though there is only a small overlap (20 nm) of the absorption of the photoinitiator with the blue light wavelengths (400-500 nm) used. A polymeric photoinitiator in which the photoinitiator moiety is attached to the phosphine oxide part of the molecule instead of the benzoyl side was also made. For this, a photoinitiator monomer where the vinyl group was attached to the phosphine oxide part, namely, 2,4,6-trimethylbenzoylphenyl-4-vinylphenylphosphine oxide (TMBVPO), was synthesized and copolymerized with DMA. The synthetic route is described in Scheme 3. From Table 1, it can be seen that the mole fraction of TMBVPO, the photoinitiator moiety, in the copolymer is the same as the mole fraction in the feed. This probably indicates a smaller difference in the monomer reactivities of TMBVPO and DMA, compared to the comonomers of PPI-1a, -1b, and -2. The resulting copolymer of TMBVPO and DMA, PPI-3, is water-soluble, as is PPI-2. In Table 5, the polymerization heat and time of the blue-light photopolymerization of HEMA/water/PPI-3 mixtures are given. The polymerization exotherm is only slightly less than those recorded for the phosphinoyl radical releasing polymeric photoinitiator PPI-2 (Table 4), but the polymerization time increases from 5 to 7 min. Thus, the polymeric photoinitiator that releases a phosphinoyl oxide radical is more efficient than the carbonyl



Table 5. Polymerization Heat of HEMA in 50 wt % Aqueous Solution Initiated by PPI-3 and Blue Light at 23 °C formulation (wt %)

mequiv/ga

50 HEMA/45 H2O/5 PPI-3d

1.6

∆H b × 102 (J/g)

conversionc (%)

polymerization time (s)

4.7

107

7

Milliequivalents of phosphine oxide per gram of photoinitiator. Heat of polymerization per gram of HEMA. Calculated as a percentage of 4.4 × 102 J/g.17 d Copolymer of 2,4,6-trimethylbenzoylphenyl-4-vinylphenylphosphine oxide (3.1 mol %) and dimethylacrylamide. a

b

Scheme 3. Synthetic Route for Polymeric Photoinitiator 3

c

light irradiaton of 20 wt % solutions of PPI-2 and PPI-3 in water in the absence of monomers are shown. Both hydrogels show high equilibrium water contents (EWCs) because of their low cross-link densities. This is due to the low photoinitiator contents of the polymers, which were 2.5 and 3.1 mol % for PPI-2 and PPI-3, respectively. The hydrogels showed no significant difference in EWCs, probably because of differences in their photoinitiator contents and molecular weights. There was, however, a difference in appearance. The hydrogel based on PPI-2 was translucent, whereas the hydrogel based on PPI-3 was clear. This transparency is indicative of a more homogeneous network and, thus, of more effective cross-linking.

Table 6. Equilibrium Water Contents of Hydrogels Made by Irradiation, for 5 Minutes, of 20 wt % Solutions of PPI-2 and PPI-3 in Water polymeric photoinitiator

PI content (mol %)

EWC (%)

appearance

PPI-2a

2.5 3.1

96 ( 1 95 ( 1

translucent transparent

PPI-3b

a Copolymer of 2,6-dimethyl-3-vinylbenzoyldiphenylphosphine oxide and dimethylacrylamide. b Copolymer of 2,4,6-trimethylbenzoylphenyl-4vinylphenylphosphine oxide and dimethylacrylamide.

radical releasing a polymeric photoinitiator.18 When the radical retained in the polymer backbone has a reduced reactivity because of its reduced mobility, it was expected that the difference between the two polymeric photoinitiators would be comparable to the difference between the carbonyl and phosphinoyl radicals. Because the efficiency difference is not that large, it can be concluded that the radical retained in the polymer backbone also initiates the reaction. Therefore, the polymer will be incorporated into the polymer network serving as a cross-linker. This is an advantage above lowmolecular-weight photoinitiators because this system does not need an additional cross-linking agent. To investigate the cross-linking abilities of the polymeric photoinitiators, polymeric photoinitiators in solution without additional cross-linker were illuminated with blue light. Hydrogels were formed. In Table 6, the equilibrium water contents and appearances of the hydrogels made by blue-

Hydrogel Formation. Determination of the photopolymerization time for the formation of a hydrogel network and characterization of the network are alternative methods in photoDSC of measuring the efficiency of a photoinitiator. For these experiments, we chose to use reactive polymers instead of monomers. For in vivo hydrogel formation, the polymerization of reactive polymers is preferred because they are less mobile and generally less toxic than monomers. Additionally, when reactive polymers are used, the gel structure can be better controlled by eliminating some reactivity ratio effects. PPI-2 was used to form hydrogels by the initiation of the photopolymerization of poly(ethylene glycol) diacrylates (PEGDAs). A PEGDA with a molecular weight of 700 (45 wt %) was polymerized in the presence of water (50 wt %) and PPI-2 (5 wt %) to form hydrogels under illumination with blue light. After polymerization, the hydrogels were extracted with water for 2 weeks, and the equilibrium water content and mass loss of the polymer network were determined. Both the equilibrium water content, which shows how much additional water the hydrogel has taken up, and the mass loss are indicative of the efficiency of hydrogel formation. If, for example, network formation has been less effective, then the cross-link density is lower. This results in a larger uptake of water. In addition, when hydrogel formation is less effective, there is a greater chance that the components, especially when low-molecular-weight components are used, are not incorporated into the network. This results in mass loss.21 In Table 7, the mass losses and additional water uptakes as functions of curing time are shown. It appears that, in the presence of PPI-2, PEGDA cured within 10 s. A suprisingly low amount of nonreacted PEGDA was extracted. The polymeric photoinitiator was very effective in forming hydrogels under the influence of blue light, making it of potential value for many applications in general and, in particular, for biomedical applications.

1278


de Groot et al.

Table 7. Hydrogels Made by Illuminating Aqueous Solutions of Polyethylene Diacrylates and PPI-2 with Blue Light at 0.5 W/cm2 formulation (wt %)

curing time (s)

EWCa (%)

mass loss (%)

45 PEGDA700b/50 H2O/5 PPI-2c 45 PEGDA700/50 H2O/5 PPI-2 45 PEGDA700/50 H2O/5 PPI-2 45 PEGDA700/50 H2O/5 PPI-2

10 30 120 150

54 ( 1 54 ( 1 54 ( 1 54 ( 1

1.7 ( 0.5 1.4 ( 0.5 0.9 ( 0.5 1.4 ( 0.5

a Equilibrium water content. b Poly(ethylene glycol) diacrylate. c Copolymer of 2,6-dimethyl-4-vinylbenzoyldiphenylphosphine oxide (2.5 mol %) and dimethylacrylamide.

The polymeric photoinitiators alone, in the absence of monomers, act as cross-linkers. Hydrogels were formed after illumination of PPI-2 and PPI-3 solutions with blue light, without the addition of an additional cross-linker. PPI-3 appeared to be more effective in cross-linking than PPI-2. PPI-2 was very effective in forming hydrogels. The high photoefficiencies and water solubilities of PPI1b, PPI-2, and PPI-3, and the extended water stability in the case of PPI-2, make these PPIs attractive candidates as bluelight photoinitiators for in vivo photopolymerizations forming hydrogels.

Conclusions Three vinyl phosphine oxide photoinitiator monomers were synthesized: 4-vinylbenzoyldiphenylphosphine oxide (VBPO), 2,6-dimethyl-3-vinylbenzoyldiphenylphosphine oxide (DMVBPO), and 2,4,6-trimethylbenzoyl(phenyl-4-vinylphenyl)phosphine oxide (TMBVPO). These vinyl-substituted acylphosphine oxides were copolymerized with the vinyl monomers dimethylacrylamide (DMA) or N-vinylpyrrolidone (NVP) and vinyl acetate (VAc) to yield polymeric photoinitiators (PPIs) containing acylphosphine oxide groups. The photoinitiator content of each PPI was between 2 and 3 mol %. The solubilities and stabilities of these vinylphosphine oxide copolymers in water were affected by the comonomer. The copolymer of VBPO-VAc-NVP (PPI-1a), although soluble, was not stable in 2-hydroxyethyl methacrylate (HEMA). The VBPO-DMA copolymer (PPI-1b) was both stable in HEMA and soluble, but not stable in water. A PPI that was both soluble and stable in water was formed by the copolymerization of DMVBPO and DMA (PPI-2). PPI-2 was very effective in forming hydrogels. Of the four PPIs synthesized, all were useful blue-light photobleaching photoinitiators, and PPI-2 was as effective as the commercially available low-molecular-weight but water-insoluble blue-light photoinitiator trimethylbenzoyldiphenylphosphine oxide (TPO, Lucirin, BASF). PPI-2 photopolymerized HEMA in aqueous solution upon exposure to blue light, with no decline in efficiency even after storage in water for 22 months at room temperature. It also formed photocured hydrogels with aqueous solutions of HEMA or poly(ethylene glycol)diacrylate. PPI-3, the copolymer of DMA with TMBVPO, which is the photoiniator monomer in which the positions of the carbonyl and phosphine oxide moieties are reversed with respect to the polymer chain as compared to those in DMVBPO, was not as efficient a photoinitiator as PPI-2.

Acknowledgment. The authors thank Syncom for the synthesis service. References and Notes (1) Matsuda, T.; Moghaddam, M. J.; Miwa, H., Sakurai, K.; Iada, F. ASAIO J. 1992, 38, M154, 1002. (2) Yasuhisa, S.; Yasuhide, N.; Yoshiaki, H.; Motosugu, S.; Matsuda, T. Ganki 1997, 48, 463. (3) Nakayama, Y.; Matsuda, T. ASAIO J. 1995, 41, M374. (4) Eliseeff, J.; Anseth, K.; Sims, D.; McIntosh, W.; Randolph, M.; Langer, R. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 3104-3107. (5) Smeds, K. A.; Grinstaff, M. W. Polym. Prepr. 2000, 41, 1722-1723. (6) Hettlich, H. J.; Lucke, K.; Kreiner, C. F. J. Cataract Refract. Surg. 1992, 20, 115-123. (7) Kessler, J. Arch. Opthalmol. 1964, 71, 412-417. (8) Haefliger, E.; Parel, J.-M. J. Refract. Corneal Surg. 1994, 10, 550555. (9) Nishi, O.; Nishi, K.; Mano, C.; Ichihara, M.; Honda, T. J. Cataract Refract. Surg. 1998, 24, 975-982. (10) Pappas, S. P. In Encyclopedia of Polymer Science and Technology; Wiley: New York, 1986; Vol. 11, p 186. (11) Baxter, J. E.; Davidson, R.; Hageman, H. J.; Overeem, T. Macromol. Chem. 1998, 189, 2769-2780 (12) Rutch, W.; Angerer, H.; Desobry, V.; Dietliker, K.; Huesler, R. In Proceedings of the 16th International Conference in Organic Coatings Science and Technology, July 9-13, 1990, Athens, Greece; Elsevier: New York, 1990; p 423. (13) Jacobi, M.; Henne, A. Polym. Paint Color J. 1985, 175, 636-639. (14) Angiolini, L.; Caretti, D.; Carlini, C. J. Appl. Polym. Sci. 1994, 21, 133-143. (15) Angiolini, L.; Caretti, D.; Carlini, C. J. Appl. Polym. Sci. 1995, 57, 519. (16) Dillingham, K.; Haitjema, H. J.; Deuring, H.; de Groot, J. H.; Hodd, K. A.; Norrby, S., to be published. (17) Lechtken, P.; Buethe, I.; Hesse, A. (BASF AG). Ger. Pat. 2,830,927, 1980. (18) Moore, J. E. Org. Coat. Plast. Prepr. 1936, 2, 747. (19) Jacobi, M.; Henne, A. Adhesion 1986, 30, 6. (20) Sumiyoshi, T.; Schnabel, W.; Henne, A.; Lechtken, P. Polymer 1985, 26, 141-146. (21) de Groot, J. H.; van Beijma, F. J.; Haitjema, H. J.; Dillingham K. A.; Hodd K. A.; Koopmans, S. A.; Norrby, S. Biomacromolecules 2001, 2, 628.

BM015584R

Hydrophilic Polymeric Acylphospine Oxide Photoinitiators

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