Amphiphilic Networks - American Chemical Society

Chapter 19

Amphiphilic Networks Synthesis and Characterization of and Drug Release from Poly(2-hydroxyethyl methacrylate)-1-polyisobutylene 1

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Béla Iván , Joseph P. Kennedy , and Paul W. Mackey

Downloaded by UNIV OF PITTSBURGH on July 2, 2013 | http://pubs.acs.org Publication Date: August 15, 1991 | doi: 10.1021/bk-1991-0469.ch019

Institute of Polymer Science, University of Akron, Akron, O H 44325-3909

Amphiphilic networks comprising poly(2-hydroxyethyl methacrylate) (PHEMA) linked (1) by polyisobutylene (PIB) segments have been synthesized by radical copolymerization of 2-(trimethylsiloxy)ethyl methacrylate (TMSEMA) with methacrylate-telechelic PIB (MA-PIBMA) followed by acid catalyzed removal of the trimethylsilyl groups. Conditions have been optimized for the synthesis of two series of PHEMA-1-PIB networks of various compositions. DSC traces exhibit a high and a low temperature T (i.e., from 98 to 111 °C and from -61 to -54 °C, respectively) which indicates microphase separation into PHEMA and PIB domains. The amphiphilic and co-continuous nature of PHEMA-1-PIB networks was demonstrated by swelling both in nheptane and water. The dry networks are transparent tough products; after swelling with water or n-heptane the swollen gels still exhibit satisfactory properties for diverse manipulation. Drug delivery systems were prepared by loading the networks with theophylline. Release studies indicate sustained drug delivery with anomalous diffusion kinetics. g

In the previous paper (1) we have described the synthesis, characterization, and certain diffusional characteristics of poly(N^V-methylacrylamide)-i-polyisobutylene amphiphilic networks exhibiting a relatively high degree of swelling in both water and η-heptane. It was of interest to prepare further neutral amphiphilic networks of lower water swelling for sustained drug delivery systems. One candidate for this N O T E : This chapter is Part IV in a series. Current address: Central Research Institute for Chemistry of the Hungarian Academy of Sciences, H-1525 Budapest, P.O. Box 17, Hungary. Corresponding author. 1

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0097-6156/91/0469-0203$06.00/0 © 1991 American Chemical Society

In Polymeric Drugs and Drug Delivery Systems; Dunn, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

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POLYMERIC DRUGS AND DRUG DELIVERY SYSTEMS


purpose is P H E M A whose utility in hydrogels has amply been demonstrated (2). Copolymerization of H E M A with M A - P I B - M A in tetrahydrofuran (THF), however, leads to massive phase separation due to the large solubility difference between the PIB and P H E M A , and homogeneous networks cannot be obtained. Phase separation during copolymerization was prevented by reducing the hydrophilicity of H E M A by exchanging the hydroxyl group with a hydrophobic trimethylsilyl group. After copolymerization (i.e., linking) the trimethylsilyl group can easily be removed yielding the desired PHEMA-i-PIB network. This paper concerns the synthesis and characterization of amphiphilic networks comprising P H E M A and PIB segments. Sustained release studies with theophyllineloaded networks are also described. Experimental Materials. 2-Hydroxyethyl methacrylate ( H E M A , Aldrich Chemical Co.) and chlorotrimethylsilane (Cl-TMS) (Lancaster Synthesis Inc.) were used as received. The source and purification of the other chemicals has been described (i). Methacrylate Telechelic Polyisobutylene Synthesis. The synthesis of a 4,000 M and a 9,500 M M A - P I B - M A has been described (7).

n

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H E M A Silylation and Removal of the - S i ( C H ) Group. Trimethylsilylation of H E M A was effected by the dropwise addition of Cl-TMS to H E M A under agitation in the presence of triethylamine as the acid acceptor in THF at 0 °C overnight (3). The triethylamine hydrochloride was removed by filtration and the T H F was evaporated by a rotovap. The product was purified by column chromatography and identified as 2-trimethylsiloxyethyl methacrylate ( T M S E M A ) by H N M R spectroscopy (i.e., appearance of the trimethylsilyl - S i ( C H ) resonance at 0.1 ppm and the disappearance of the hydroxyl -OH resonance at 3.3 ppm). The purity of the T M S E M A was determined to be 99% using a Perkin-Elmer 8410 gas chromatograph by the decrease in the retention time of the silylated monomer. The removal of the - S i ( C H ) group was carried out by adding a 5 times excess of HC1 to a methanol solution of the monomer. The progress of the reaction was followed using G C by the shift to longer retention time for H E M A versus the T M S E M A monomer. 3

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P o l y m e r i z a t i o n of T M S E M A and D e s i l y l a t i o n of P T M S E M A . P o l y ( 2 (trimethylsiloxy)ethyl methacrylate) (PTMSEMA) was prepared by the free radical polymerization of T M S E M A in THF ((TMSEMA)=1.5M, (AIBN)=1.125x10^, 60 °C, 8 hrs). The homopolymer was precipitated into cold methanol and dried. The removal of the - S i ( C H ) group of the homopolymer was carried out at room temperature by dissolving 1 gram of P T M S E M A in a 5% HC1 methanol solution using a 5 times excess of HC1. The reaction was run for 4 days with a 25 mL aliquot being withdrawn each day. The aliquot was purified by dialysis (methanol solution against water, 24 hours, 1000 molecular weight cut-off dialysis tubing). Following dialysis the polymer was dissolved in methanol and precipitated into π-pentane. The 3

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19.

IVAN ET AL.

Poly(2-hydroxyethyl methacrylate)-1-polyisobutylene

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extent o f the r e a c t i o n was determined using a G e m i n i 200 * H N M R spectrophotometer by the appearance of the - O H resonance at 3.3 ppm and the disappearance of the -Si(CH )3 resonance at 0.1 ppm. 3

Network synthesis. The procedure and equipment used to prepare the networks have been described (7). Experimental data and conditions are given in Table I. The abbreviations in the sample column have been explained in the previous paper (7). The letter (H) denotes the hydrophilic moiety 2-hydroxyethyl methacrylate. The removal of the -Si(CH )3 group was accomplished by swelling the networks in a 5% solution of HC1 in methanol for two days, followed by swelling in 5% HC1 in 2methoxyethanol for two days. The HC1 solution was changed daily. Finally, the networks were soxhlet extracted sequentially with hexanes and ethanol for 24 hrs each to remove all unreacted M A - P I B - M A , monomers, homopolymers, and desilylation byproducts. This order of extraction insures the removal of all extraction solvents by soaking in water prior to biological testing.


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Network Characterization. The networks were characterized by DSC (DuPont 1090 Thermal Analyzer) under nitrogen at a heating rate of 20 °C/min. Prior to the experiment the samples were preheated to 130 °C, equilibrated for 10 minutes and cooled to room temperature at 1 °C/min. Swelling experiments were conducted as described (7). Release experiments. The methodology of release experiments has been described ω. Results and Discussion Synthesis. The procedures used for the preparation of other amphiphilic networks (1) could not be used for the synthesis of PHEMA-I-PIB because of the insolubility of P H E M A in solvents that dissolve PIB e.g., THF. The above described silylationdesilylation procedure was designed to provide mutual solubility of the phases and thus to make the synthesis possible. Desilylation model studies were carried out on both the silylated monomer and polymer to develop suitable reaction conditions. The desilylation of the T M S E M A was instantaneous as indicated with G C by the increase in the retention time of the monomer. The desilylation the P T M S E M A was equally facile as determined by *H N M R spectroscopy; Figure 1 shows the disappearance of the -Si(CH )3 resonance at 0.1 ppm and the appearance of the -OH resonance at 3.3 ppm without detectible ester hydrolysis even after four days. Table I summarizes the conditions used for network synthesis. The amount of T M S E M A was determined by the amount of H E M A required for a desired composition. The A I B N concentrations were kept low to insure adequate chain growth during the copolymerization (that is network formation). The obtained networks were transparent, homogeneous, tough, flexible materials demonstrating the utility of the approach. Desilylation of the networks was carried out by the use of 3


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POLYMERIC DRUGS A N D DRUG DELIVERY SYSTEMS

Table I. Experimental Conditions for the Synthesis of PHEMA-1-PIB Amphiphilic Networks

PIB (g)


Sample

H-4-29 H-4-37 H-4-49 H-4-57 H-4-68 H-9.5-38 H-9.5-46 H-9.5-54 H-9.5-64 H-9.5-75

MA End Group (molxlO ) 4

0.6 0.8 1.0 1.2 1.4 0.6 0.8 1.0 1.2 1.4

3.08 4.10 5.13 6.15 7.18 1.26 1.68 2.11 2.53 2.95

HEMA (g)

HEMA (molxlO )

TMSEMA (g)

AIBN (molxlO )

1.4 1.2 1.0 0.8 0.6 1.4 1.2 1.0 0.8 0.6

10.76 9.22 7.68 6.15 4.61 10.76 9.22 7.68 6.15 4.16

2.18 1.87 1.55 1.24 0.93 2.18 1.87 1.55 1.42 0.93

1.66 1.18 0.86 0.54 0.32 1.62 1.15 0.84 0.53 0.31

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THF solvent; total volume 8 mL, 72 hours, 60°C.

CH, -

Amphiphilic Networks - American Chemical Society

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