High-Strength, Melt Processable, Aromatic Poly(anhydride) - American

Chapter 5

High-Strength, Melt Processable, Aromatic Poly(anhydride)s

Downloaded by COLUMBIA UNIV on August 5, 2012 | http://pubs.acs.org Publication Date: March 28, 2008 | doi: 10.1021/bk-2008-0977.ch005

Kevin Cooper and Angelo Scopelianos Center for Biomaterials and Advanced Technologies, Medical Devices Group, A Division of Ethicon Inc., A Johnson & Johnson Company, Route 22 West, Somerville, NJ 08876

A synthetic technique for preparing aromatic poly(anhydride)s with high molecular weights has been developed that yields polymers with high tensile properties and melt processability. The high molecular weight aromatic poly(anhydride)s (inherent viscosities greater than 1.0 dl/g) were prepared by a three-step synthesis in which highly pure aromatic dicarboxylic acids were converted to highly pure dianhydrides followed by high temperature melt polycondensation to form the polyanhydrides. It has been determined that these high molecular weight poly(anhydride)s have excellent thermal stability, are melt processable, yield high strength fibers and molded articles, and are radiation sterilizable.

© 2008 American Chemical Society In Polymers for Biomedical Applications; Mahapatro, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.

51


52 In the 1930's, Carothers prepared a series of aliphatic poly(anhydride)s for potential use as fibers in the textile industry (1). However, the hydrolytic stability of these materials was very poor. By the mid-1950's, Conix was able to synthesize aromatic poly(anhydride)s with improved film and fiber forming properties (2). Despite these properties, the polyanhydrides' poor thermal and hydrolytic stability resulted in their limited use, and no commercial applications were found. By the late 1960's, however, hydrolytic instability became an important factor for polymers utilized in the manufacture of medical devices such as absorbable sutures and drug delivery systems. By the early 1970's, Domb and Langer determined that not only were aromatic poly(anhydride)s hydrolytically unstable, but under certain circumstances followed zero-order drug release breakdown kinetics via surface erosion (3a, b). This, along with the fact that aromatic poly(anhydride)s have been shown to degrade into monomeric diacids which are highly biocompatible, led to their use as matrices for controlled delivery of biologically active substances. However, due to the low molecular weights, degradation and gelation as well as poor thermal stability and melt processability, Domb and Langer's aromatic poly(anhydride)s have been restricted to the narrow field of drug delivery, where microspheres of the drug in the polymer matrix can be prepared at low (ambient) temperatures utilizing solvent casting techniques. High molecular weight, thermally stable, melt processable aromatic poly(anhydride)s are required for biomedical devices such as staples, clips, and sutures since superior mechanical properties are a necessity for good product results. Good polymer mechanical properties are a requirement for certain biomedical devices such as staples, clips, and sutures. These devices are advantageously made by traditional melt processing techniques such as injection molding or fiber extrusion. To be able to achieve the high mechanical properties required, the polymer must generally be high molecular weight. To utilize melt processing fabrication techniques, the resin must have excellent melt stability; that is to say it must not degrade at temperatures at which it can be rendered molten. We describe in this work the preparation of high molecular weight aromatic poly(anhydride)s that exhibit excellent melt stability and have been fabricated into high strength test articles. In addition, in-vitro experimental evidence is provided that strongly suggests that materials may provide higher invivo strength retention than is possible with bulk erosion bioerodible polymers such as poly(glycolide). Also, since the practice of sterilization of biomedical devices by ethylene oxide is diminishing due to concerns for the environment, along with health and safety factors, it may also be necessary for future biomedical devices to be irradiation sterilizable (i.e., Cobalt/gamma, E-beam). From work at Ethicon on polymers with aromatic substituents in the backbone (4a,b), it is believed that aromatic groups lead to an enhancement in the radiation stability of a polymer.

In Polymers for Biomedical Applications; Mahapatro, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.


53 Therefore, aromatic poly(anhydride)s may prove useful for their potential as irradiatable devices. Despite the desirability of such a polymer, the development of high molecular weight (I.V. >1.0 dl/g), non-crosslinked, non-gel forming, bioerodible aromatic poly(anhydride)s incorporating these properties has not progressed. This report describes for the first time a process for preparing high molecular weight (I.V. > 1.0 dl/g), non-crosslinked, non-gel forming, high strength, thermally stable, melt processable and irradiation sterilizable, aromatic poly(anhydride)s. In detail, a synthetic technique for preparing aromatic poly(anhydride)s with high molecular weights, as characterized by inherent viscosities, in excess of 1.0 dl/g in chloroform at room temperature (25°C) has been developed. In this synthetic process, the high molecular weight aromatic homo or copoly(anhydride)s (I.V. > 1.0 dl/g) were prepared by a three-step synthesis. The high molecular weight aromatic poly(anhydride)s were synthesized from highly pure aromatic dianhydrides that were prepared from highly pure aromatic dicarboxylic acids. The highly pure dicarboxylic acid was formed in the first step by a nucleophilic substitution reaction between a hydroxybenzoic acid and a dibromoalkane. Batch sizes of up to half a kilogram have been prepared. Once a salt free product was obtained it was then further purified by three recrystallizations with N-methylpyrrolidinone (NMP) or dimethylacetamide (DMAC). The highly pure aromatic dicarboxylic acid was then refluxed with acetic anhydride for several hours to form a highly pure aromatic mixed anhydride. This was followed by recrystallization with acetic anhydride, isolation and drying. Batch sizes of up to 150 grams have been prepared by this method. The isolated, pure, dry mixed anhydride was then polymerized under melt condensation conditions at temperatures between 180°C and 240°C for a time of 90 to 360 minutes utilizing high vacuum ( 1.0 dl/g), non-crosslinked, non-gel forming, aromatic poly(anhydride) homo and co-polymers are prepared from monomers l,6-bis(pcarboxyphenoxy)hexane, 1,4-bis(pcarboxyphenoxy)butane, and 1,2-bis(pcarboxyphenoxy)ethane. It was also determined that some of the high molecular weight poly(anhydride)s display a linear decrease in breaking strength, while all showed excellent thermal stability and melt processablility. They also exhibit excellent radiation stability and have yield strengths similar to or greater than that of poly(p-dioxanone) molded articles.

Results and Discussion The preparation of poly(anhydride)s can be considered a three-step process in which an aromatic dicarboxylic acid is formed in the first step followed by the



54 preparation of a mixed anhydride which is then melt polymerized by a method initially described by Carothers (I). This method was then modified by Domb and Langer (3,5). From the methods described by Domb and Langer, high molecular weight (I.V. > 1.0 dl/g) aliphatic poly(anhydride)s have been prepared. However, only low molecular weight (I.V. < 0.55 dl/g) fully aromatic homo and copoly(anhydride)s can been synthesized by Domb and Langer's methods, due to the formation of a rubbery gel, which swells extensively in chloroform. This is explained by a depolymerization process during extensive heating that yields entangled cyclic macromers (3d). Domb and Langer state that the depolymerization process occurs at longer polymerization times and higher polymerization temperatures. Consequently, it was believed that high molecular weight (I.V. > 1.0 dl/g) fully aromatic homo and co-poly(anhydride)s could not be prepared due to the longer reaction times and higher reaction temperatures necessary to polymerize the higher glass/melting transition aromatic poly(anhydride)s. In the results described herein, it has been determined that high molecular weights can be obtained for aromatic homo or co-poly(anhydride)s if high purity monomers are utilized along with higher melt polymerization temperatures and longer reaction times. Hence, it was concluded that the dicarboxylic acid prepared in the first step of the three-step polymerization synthesis must be of the highest purity (99.9%). This was successfully established by first preparing an "ash free", salt free acid product (Example 1). The salt free monomer was prepared by suspending the highly insoluble sodium salt in a strongly acidic aqueous solution. This procedure was repeated one to two more times, since it was found that 10 to 15 percent ash remained after one treatment (Elemental analysis, Table 1). Once ash free monomer had been prepared, the dicarboxylic acid was purified by three recrystallizations using N-methylpyrrolidinone (NMP) or dimethylacetamide (DMAC) as a solvent (Examples 1 and 4). This was necessary, since it was determined by NMR that the purity after the first and second recrystallizations was not polymer grade. It was also necessary to wash the purified acid monomer after the third recrystallation with hot, distilled water to remove NMP bound to the acid. However, as can be seen in Example 4, recrystallization with DMAC yielded a complex of the solvent bound to the acid which could not be removed by washing with hot water (Table 1). Nevertheless, high molecular weights were obtained (Table 2). This will be discussed in greater detail in later descriptions. Whether the purified acid was recrystallized with NMP or DMAC, it was washed in the final preparation step with acetone for ease of drying. In contrast, Domb and Langer prepared the bis(p-carboxyphenoxy)alkanes according to the method described by Conix (6) and purified by extraction with ether before use, leaving the monomers impure (Example 8). It would appear


55


Table 1. Carbon, Hydrogen and Nitrogen elemental analysis of bis-l,n-(p-carboxyphenoxy)alkane aromatic acids Aromatic Acid 1,6-NMP Complex 1,6-Free Acid 1,4-Free Acid

Theoretical H C

N

Found* H C

N

63.1

7.51

5.26

62.76

7.46

5.44

NMP

67.0

6.19

0

66.92

6.11

0

NMP

65.4

5.48

0

65.06

5.42

0

Recrystallization Solvent NMP

Swarzkopf Microanalytical Labs

Table 2. Inherent Viscosities of poly[l,6-bis(carboxyphenoxy)hexane anhydride] as a function of time (minutes) at a reaction temperature of200°C Experiment A B C D E F G

Recrystallization Solvent NMP NMP NMP NMP DMAC DMAC DMAC

a

120 l.l

a

160

200

a

240

a

b

b

1.2 1.4

b

b

1.3 l.l

b

b

1.3

a

Reaction Time (minutes), inherent Viscosity (dl/g)


b

1.3


56 that impurities remaining after this process partially contribute to the lower molecular weight (I.V. < 0.5 dl/g) aromatic bis(p-carboxyphenoxy)alkane poly(anhydride)s synthesized in the past. We have repeated this procedure, and have found our molecular weights to be less than 0.3 dl/g, similar to Domb and Langer's results (Table 7). As expected, the results indicate that purification by recrystallization with NMP leads to higher molecular weights at a reaction temperature of 180°C (I.V. > 0.60 dl/g). Purification by washing with a nonsolvent (acetone/ether, i.e., Domb's method) leads to low molecular weights (0.2 to 0.3 dl/g), even at higher reaction temperatures (200°C). Therefore, by purifying the acid and using higher reaction temperatures and longer reaction times, it is possible to obtain much higher molecular weights. Once our purified dicarboxylic acid monomer had been synthesized, isolated and purified, the mixed anhydride was prepared (Examples 2 and 5). The mixed anhydride is synthesized by reacting acetic anhydride with the acid monomer at reflux for several hours under a nitrogen atmosphere followed by removal of a portion of the acetic anhydride. The homogeneous solution was then allowed to crystallize at 0°C overnight, filtered, and then washed with dry ethyl ether to remove traces of acetic anhydride. The mixed anhydride was then filtered, and dried for 24 hours at low temperature (50°C) under vacuum to yield the highly pure anhydride monomer. Recrystallization with acetic anhydride was also performed (Example 5). Domb and Langer state that the acid monomer is refluxed in acetic anhydride for 15 minutes and then the unreacted diacid (10-20%) was removed by filtration (3a). As discussed above, it is unclear as to the quantity of trace amounts of the impurity, the diacid, that might remain after filtration (Example 8). This would lead to an anhydride monomer that is impure and, therefore, cannot be polymerized to high molecular weight. Our isolated, pure, dry mixed anhydride was then polymerized under typical melt condensation conditions, utilizing elevated temperatures (200°C to 220°C) under high vacuum with reaction times ranging from 90 to 360 minutes. Under these conditions, high molecular weights (Examples 3, 6 and 9) were formed. Domb and Langer stated that polymerizing at temperatures above 180°C for greater than 150 minutes not only leads to the formation of insoluble gel, but a decrease in molecular weight with the formation of insoluble gel through a depolymerization process that yields cyclic macromers. No decrease in molecular weight or the formation of insoluble gel was observed with our aromatic poly(anhydride) polymerizations at even higher temperatures (i.e., 200 to 220°C). NMR and FT-IR also indicates no formation of branching, crosslinking or degradation side products (Figure 3). Inherent viscosities as high as 1.4 dl/g (Tables 2 and 7, Figure 5) were found. This clearly indicates that high molecular weight (I.V. > 1.0 dl/g) aromatic homo and co-poly(anhydride)s can be synthesized. In fact, recrystallization of the anhydride monomer (Example 5) along with the recrystallization of the diacid by


57 DMAC (Example 4), also leads to high molecular weights (Table 2) without the formation of gel or crosslinking. To examine the potential of these high molecular weight aromatic poly(anhydride)s for melt processing methods such as injection molding and melt extrusion, melt stability measurements were made. Typically the resin was introduced and packed into the barrel of a capillary rheometer at a temperature just below the melting point of the resin. The barrel temperature setting was then reset and quickly brought up to the test temperature, while continuing to lower the piston to facilitate packing. A clock was started as soon a set temperature was reached. With a die diameter and piston speed combination selected to result in a shear rate of about 100 sec" , piston travel was activated (once the barrel had equilibrated to the test temperature) to obtain an initial viscosity measurement. Once a value was obtained, the piston travel was arrested and the remaining polymer melt was allowed to reside in the temperature-controlled rheometer barrel. After about 10 minutes, the piston travel was again reactivated and a second measurement made. This start-and-stop procedure was employed until at least six data points were obtained over the course of about one hour, A plot of log melt viscosity versus total residence time in the barrel at the test temperature was found to be linear. The slope value was used to calculate the percent change in melt viscosity with unit time. A cone and plate rotational rheometer was often employed with similar results. Melt viscosity (i.e., molecular weight) remained constant over a one-hour period under an inert, dry nitrogen atmosphere at 220°C (Figure 5). This is a strong indication that degradation/gelation does not occur at processing temperatures above 200°C. This had not been previously established for aromatic poly(anhydride)s.


1

Additionally, monofilament fibers were produced using a capillary rheometer as an extruder. The ground resin was introduced and packed into the barrel as described above. Typically a 40-mil die with an L/D of 25 was used. A piston speed was selected to result in a shear rate of 236 sec" . The extrudate was passed through an ice-water quench bath and subsequently collected on a roll at constant speed. A jet-stretch of about 4 was used to get an extrudate diameter of about 20 mils. The spool of extrudate was typically placed into a vacuum oven for drying and storage purposes. To develop mechanical strength in the fiber, molecular orientation was imparted by drawing the extrudate. The fiber was stripped from a supply spool at constant speed using a first set of pinch rollers. The fiber was then directed by a series of rollers into a glycerin bath heated to a preset temperature; since the fiber was passed through a second set of pinch rollers rotating at a higher speed, a draw tension was established that caused permanent deformation of the fiber. The deformation, or drawing, occurred in the glycerin bath. The draw ratio can be calculated by dividing the linear speed of the fiber exiting the bath by the linear supply speed. The exiting fiber was in-line water-washed and subsequently dried and stored under vacuum. 1


58 If the fiber was annealed, it was racked wound and heated under nitrogen at the annealing temperature. Using the above conditions at an extrusion temperature of 250°C, and a shear rate of 236 sec" , a poly[l,4-bis(p-carboxyphenoxy)butane] resin displayed a melt viscosity of approximately 28,000 poise. The 18 to 19.5 mil diameter monofilament extrudate was taken-up through an ice-water quench and subsequently drawn 4X at I00°C resulting in a 9.6 mil fiber (Table 3). This fiber was subjected to a higher temperature (105°C) second-stage draw at 1.105X resulting in slightly higher strength and lower elongation. A sample of po!y[l,4-bis(p-carboxyphenoxy)butane-co-l,6-bis(p-carboxyphenoxy)hexane] exhibiting a melting point of 170°C was extruded using similar conditions as described above. Using an extrusion temperature of 270°C, and a shear rate of 236 sec" , the resin displayed a melt viscosity of approximately 11,000 poise. The monofilament extrudate was taken-up through an ice-water quench. The extrudate was subjected to a two-stage drawing process, 5X at 84°C immediately followed by 2X at 112°C resulting in an 8.1 mil fiber. This 10X fiber was subjected to a further draw at 1.368X conducted at 106°C, again resulting in slightly higher strength and lower elongation (Table 3). Cylindrical dumbbells were also prepared at high temperatures (220 to 260°C) utilizing a CSI Mini-max small injection molder to determine baseline as well as in-vitro (pH=7.27, 37°C) physical properties. For example, the poly[bisl,6(p-carboxyphenoxy) hexane anhydride], 1,6 PA, was processed at 220°C. 1,6 PA processed at 220°C, was still soluble (i.e., no gelation), and had no observable changes in chemical structure as determined by NMR (Figure 4). The mechanical properties as well as in-vitro testing of cylindrical dumbbells were also studied (Tables 4-6 and 8-14). As can be seen from the tables, the yield strength and modulus of the aromatic poly(anhydride)s developed by the methods described herein are similar to or greater than poly(pdioxanone), an absorbable polyester used extensively for medical devices, and poly(anhydride)s described by other researchers. This is another indication that the aromatic poly(anhydride)s have the high molecular weights (I.V. > 1.0 dl/g), and consequently, the high strengths required in wound closure devices. As stated earlier, it was believed that aromatic poly(anhydride)s would be cobalt sterilizable since previous work at Ethicon (4a,b) established that incorporation of aromatic subtituents in the polymer backbone yielded irradiation stability. Consequently, test coupons of the aromatic poly(anhydride)s were subjected to cobalt (gamma) irradiation. No loss in the strength or modulus was observed. Also, no observable chemical structural changes were found by NMR (Figure 6). Molecular weight (I.V.) and solubility was also unchanged for coupons (Table 4). Therefore, it has been established that our aromatic poly(anhydride)s can be cobalt irradiated without loss in physical properties, molecular weight (I.V), solubility, or changes occurring in chemical structure (NMR).


1

1


59

Table 3. Fiber Tensile Properties of Aromatic Poly(anhydride)s as a Function of Draw Ratio


PA

1,4 l,4-co-l,6

Draw Ratio

Dia. (mil)

4X 4.42X 10X 13.68X

9.6 8.8 8.1 6.7

Straight Tensile Str. (kpsi) 45.45 52.12 52.20 57.06

Knot Tensile Str. (kpsi) 33.57 37.65 29.30 40.84

Elong to Break (%) 26 14 38 23

Young's Modulus (kpsi) 363 339 374 394

Table 4. Physical properties of annealed of poly[l,6bis(carboxyphenoxy)hexane anhydride]

Unannealed Annealed* 1 wk in-vitro 3 wk in-vitro 6 wk in-vitro Annealed, Irradiated (2.5Mrad) Irradiated, 1 wk in-vitro Irradiated, 3 wk in-vitro Irradiated, 6 wk in-vitro

Strength Retained (%)

9.5 7 6.6 5.8 3.2 6

Tensile Modulus (psi) 44000 76000 75500 58000 43000 75000

6200

8

77500

100

5100

6.3

70000

85

2500

3.6

39000

42

Tensile Strength (psi) 4500 5600 5000 3700 2100 5900

Elongation@ Yield (%)

•Annealing 85°C/6hrs., data an avg. of 8-12 cylindrical dumbbells


— —

88 66 35 100

60


Table 5. Physical properties of unannealed of poly[l,4-bis(carboxyphenoxy)butane anhydride]

Unannealed 1 wk in-vitro 3 wk in-vitro 6 wk in-vitro 9 wk in-vitro Unannealed, Irradiated 2.5Mrad Irradiated, 1 wk in-vitro Irradiated, 3 wk in-vitro Irradiated, 6 wk in-vitro Irradiated, 9 wk in-vitro


11.5 9.3 9.6 8.7 3 8


6500

9.5

79000

100

6500

9.2

80000

100

4800

6

59000

74

2200

3.3

55000

30


Elongation® Yield (%)

—

85 90 73 24 88

Table 6. Physical properties of annealed of poIy[l,4-bis(carboxyphenoxy)butane anhydride]

Annealed 1 wk in-vitro 3 wk in-vitro 6 wk in-vitro 9 wk in-vitro Annealed, Irradiated 2.5Mrad Irradiated, 1 wk in-vitro Irradiated, 3 wk in-vitro Irradiated, 6 wk in-vitro Irradiated, 9 wk in-vitro


11.1 9 6 2 1 8


6500

8

81000

76

3400

3

100000

40

2500

2

105000

30

1800

2

105000

21



Data an avg. of 8-12 cylindrical dumbbells


—

80 52 30 17 98


61 Even though no loss in physical properties was observed for aromatic poly(anhydride)s subjected to gamma irradiation, it is important to establish the polymers physical characteristics as a function of exposure time in-vitro. This is a necessary requirement, since past work has shown that absorbable polymers, and devices formed from them (PDS™, Vicryl™), subjected to cobalt may indicate little change in physical properties, but when tested in-vitro rapidly lose strength. However, no difference is observed in in-vitro properties between coupons subjected to cobalt versus unirradiated coupons. In fact, yield strength as a function of weeks in-vitro appears to follow a linear decrease profile for annealed test coupons. However, unnanealed test coupons display an induction period (6 weeks) prior to the linear decrease in physical strength. Like the 1,6 PA, poly[l,4-bis(p-carboxyphenoxy)butane anhydride] (1,4 PA) was also molded into cylindrical dumbbells, and baseline as well in-vitro physical properties were determined (Tables 5, 6 and 8-10). As can be seen from these tables, the yield strength and modulus is greater than that of 1,6 PA. This is as expected, since the 1,4 PA contains two less methylene groups per repeat unit. This leads to a polymeric chain, which is slightly stiffer and, therefore, causes a corresponding increase in yield strength and modulus. More importantly, like the 1,6 PA, unannealed test coupons of the 1,4 PA display no change in physical strength between coupons subjected to cobalt and unirradiated test samples. In addition, like the 1,6 PA an induction period in the in-vitro physical strength is observed. However, unlike the 1,6 PA, the 1,4 PA displays only a 3 week induction period, followed by a linear decrease strength profile. The nature of this difference between 1,6 PA and 1,4 PA is believed to be due to the increased hydrolyzability and hydrophilicity of the 1,4-bis acid in comparison to that of the 1,6-bis acid monomer. It should be noted that similar behavior to that of the annealed 1,6 PA is observed for annealed coupons of the 1,4 PA. Additionally, 1,4 PA subjected to a dosage of 4.5 Mrad shows almost identical in-vitro results to that of 1,4 PA subjected to 2.5 Mrad (Table 8). This is another clear indication that this series of poly(anhydride)s are radiation sterlizable. Also of significance, is the establishment that the 2.5 Mrad in-vivo BSR profile for the 1,4 PA is almost identical to that of the 2.5 Mrad in-vitro BSR profile. This indicates that for the polyanhydride systems studied, in-vitro BSR results can be correlated to in-vivo BSR results. Physical properties of poly[l,2-bis(p-carboxyphenoxy)ethane anhydride] (1,2 PA) were also determined. Unannealed test coupons gave results at baseline (zero day) of a yield strength of 11300 psi, a yield at elongation of 13%, and a modulus of 114500 psi. As expected, the strength and modulus of the 1,2 PA, in comparison with 1,6 PA and 1,4 PA, increased. Results also indicate that little change (< 10% decrease) occurs in the strength and modulus in the first week invitro, but is followed by a sharp decrease in strength at 3 weeks (33% retained


62


Table 7. Inherent Viscosities of poly|l,6-bis(carboxyphenoxy)hexane anhydride) as a function of time (minutes) at a reaction temperature of 180 or 200°C Experiment A B C (Control) D (Control)

Recrystallization Solvent NMP NMP None None

a

120 min l.l c

b

0.7 0.2

a

240 min

a

240 min

a

120 min 0.7

C

1.3

b

0.25

b

0.2 a

c C

0.3

b

b

Controls performed via Domb and Langer, Reaction Time, Inherent viscosity (dl/g) at 180°C, inherent viscosity (dl/g) at 200°C

Table 8. Physical properties of unannealed of po!y[l,4-bis(carboxyphenoxy)butane anhydride] irradiated at 4.5Mrad

Unannealed 1 wk in-vitro 3 wk in-vitro 6 wk in-vitro 9 wk in-vitro

Tensile Strength (psi) 7000 6800 6900 4200 1200

Elongation® Yield (%) 11 11 9.8 8 2

Tensile Modulus (psi) 71000 63000 76000 43000 56000




—

97 99 60 17

63


Table 9. In-vivo physical properties of unannealed of poly[l,4-bis(carboxyphenoxy)butane anhydride] Tensile Strength (psi) 7800 7000 7400 5900 2800 7900


Unannealed 1 wk in-vivo 3 wk in-vivo 6 wk in-vivo 9 wk in-vivo Unannealed, Irradiated 2.5Mrad Irradiated, 6900 1 wk in-vivo Irradiated, 7400 3 wk in-vivo Irradiated, 5700 6 wk in-vivo Irradiated, 2000 9 wk in-vivo Data an avg. of 8-12 cylindrical dumbbells


11.3 11.1 10 10 5.7 10.6


10.3

81000

87

10

82000

94

9

98000

73

5.6

10000

25

—

90 95 75 35 100

Table 10. Physical properties of unannealed of po!y|l,4-bis(carboxyphenoxy)butane anhydride]

Unannealed 1 wk in-vitro 3 wk in-vitro 6 wk in-vitro

Tensile Strength (psi) 6300 5600 6300 5400

Elongation® Break (%) 84 78 56 18

Tensile Modulus (psi) 62000 55000 58000 70000




—

90 100 85

64 Table 11. Physical properties of unannealed of poly[l,6-bis(carboxyphenoxy)hexane anhydride]


Unannealed 1 wk in-vitro 3 wk in-vitro 6 wk in-vitro 9 wk in-vitro

Tensile Strength (psi) 5500 5700 6200 5500 4500

Elongation® Break (%) 120 135 155 77 10

Tensile Modulus (psi) 79000 49000 54000 56000 50000

Strength Retained (%) —

100 100 100 75


strength) (Table 12). This is as expected, since it is believed, from the literature, that the 1,2 PA is even more hydrophilic than the 1,4 PA or 1,6 PA. In fact, although the modulus is not as high as BTC-1 (4a, b) and PGA, this type of yield strength breakdown profile appears to be quite similar to radiation sterilizable BTC-1, and ethylene oxide sterilized PGA (Tables 13, 14). In conclusion, we have developed a process by which high molecular weight homo and co-poly (anhydride) polymers (I.V. > 1.0 dl/g) can be synthesized at polymerization temperatures above 200°C without degradation or gelation at reaction times greater than 300 minutes by utilizing highly purified dicarboxylic acid and anhydride monomers under highly inert, high vacuum (< 10 microns) conditions. Also, the high molecular weight poly(anhydride)s are melt processable under inert atmospheric conditions at temperatures greater than 200°C. The high molecular weight poly(anhydride)s are also stable to Cobalt irradiation without loss of mechanical properties, molecular weight, or changes in chemical structure. The aromatic poly(anhydride)s also display various physical strength breakdown profiles, from that of low strength/slow breakdown (i.e., 1,6 PA) to that of high strength/fast breakdown (i.e., 1,2 PA), with behavior between the two extremes (i.e., 1,4 PA).

Experimental The present report describes a synthetic process for preparing aromatic poly(anhydride)s, potentially useful as biomedical devices, with high molecular weights as characterized by inherent viscosities in excess of 1.0 dl/g in common organic solvents such as chloroform at ambient (25°C) temperature.


65


Table 12. Physical properties of unannealed of poly[l,2-bis(carboxyphenoxy)ethane anhydride]

Unannealed 1 wk in-vitro 3 wk in-vitro 4 wk in-vitro Data an avg. of 8-12

Tensile Elongation® Strength Yield (%) (psi) 11300 12.9 9900 10.6 3700 4.1 1500 2 cylindrical dumbbells

Tensile Modulus (psi) 114000 116000 74000 56000

Strength Retained (%) —

88 33 13

Table 13. In-vivo physical properties of annealed BTC-1

Annealed 1 wk in-vivo 2 wk in-vivo 3 wk in-vivo 4 wk in-vivo Annealed, Irradiated 2.5Mrad Irradiated, 1 wk in-vivo Irradiated, 2 wk in-vivo Irradiated, 3 wk in-vivo Irradiated, 4 wk in-vivo


12 42 24 5 4 9


10700

41

160000

58

8100

12

98000

44

2100

6

42000

11

0

0

0

0





—

60 57 16 7 96

66


Table 14. In-vivo physical properties of annealed PGA

Annealed 1 wk in-vivo 2 wk in-vivo 3 wk in-vivo 4 wk in-vivo Annealed, Irradiated 2.5Mrad Irradiated, 1 wk in-vivo Irradiated, 2 wk in-vivo Irradiated, 3 wk in-vivo Irradiated, 4 wk in-vivo


13 33 6 0 0 11


10000

7

48000

52

3200

7

39000

17

0

0

0

0

0

0

0

0



—

76 29 0 0 100


In this synthetic process, the high molecular weight poly(anhydride) was prepared by a method consisting of selecting a highly pure aromatic mixed anhydride that was synthesized by reacting acetic anhydride at reflux under a stream of nitrogen for several hours with a highly pure dicarboxylic acid. The anhydride was then isolated, purified, and dried. It was then polymerized under melt condensation conditions at temperatures between 180°C and 240°C for a time of 90 to 360 minutes utilizing high vacuum (< 20 microns) to remove the condensation product formed during the polymerization. The various times and temperatures of the polymerization collaborate to yield aromatic homo- and co-poly(anhydride)s with high molecular weights (I.V. > 1.0 dl/g). In the examples, higher molecular weight (I.V. > 1.0 dl/g), noncrosslinked, aromatic homo and co-poly(anhydride) polymers were prepared from 1,6-bis(pcarboxyphenoxy)hexane, l,4-bis(p-carboxyphenoxy)butane, and 1,2-bis(p-carboxyphenoxy)ethane. The polymers and monomers were characterized for chemical composition and purity (NMR, FT-IR, elemental analysis), thermal analysis (DSC), melt rheology (melt stability and viscosity), molecular weight (inherent viscosity), crystallinity (XRD). Baseline and in-vitro mechanical properties (Instron stress/strain) were determined on molded and extruded samples.


67 FT-IR was performed on a Nicolet FT-IR. Polymer samples were melt pressed into thin films. Monomers were pressed into KBr pellets. H NMR was performed on a 200 MHz NMR using CDC1 as a reference. Elemental analysis was performed at Schwarzkopf Microanlytical Laboratories. Thermal analysis of polymers and monomers was performed on a Dupont 912 Differential Scanning Calorimeter (DSC) at a heating rate of 10°C/min. A Fisher-Johns melting point apparatus was also utilized to determine melting points of monomers. Thermal gravimetric analysis was performed on a Dupont 951 TGA at a rate of 10°C/min. under a nitrogen atmosphere. A Rheometrics Dynamic Analyzer RDA II also determined isothermal melt stability of the polymers for a period of 1 hour at temperatures ranging from 220°C to 260°C under a nitrogen atmosphere. Melt viscosity was also determined utilizing a Rheometrics Dynamic Analyzer RDA II at temperatures ranging from 160°C to 290°C at rate of l°C/min. to 10°C/min. atfrequenciesof lcm" to 100cm" under a nitrogen atmosphere. Inherent viscosities (I.V.) of the polymers were measured using a 50 bore Cannon-Ubbelhode dilution viscometer immersed in a thermostatically controlled water bath at 25°C at a concentration of 0.025 gms/25 ml. The cylindrical dumbbells were prepared by utilizing a CSI Mini-max injection molder equipped with a dry nitrogen atmospheric chamber at temperatures rangingfrom220°C to 260°C with a residence time of 3 minutes. The aromatic poly(anhydride)s were also extruded into fibers. For example, a sample of poly[l,4-bis(p-carboxyphenoxy)butane] exhibiting a melting point of 190°C was extruded using an Instron capillary rheometer equipped with a 40-mil die with an L/D of 25. Baseline and in-vitro mechanical properties of the cylindrical dumbbells of the poly(anhydride) polymers so produced were performed on an Instron model 1122 at a crosshead rate of 0.35 in/min. Specimen gauge length was 0.35 in., with a width of 0.06 in. Results are an average of 8 to 12 dumbbell specimens. In-vitro studies were determined in a buffer solution (pH=7.27) at a temperature of 37°C for periods of 1, 3, 6, and 9 weeks. Eight to ten cylindrical dumbbells (2.4 to 3.0 grams) were placed in 100 ml of buffer solution. The buffer solution was replaced on a weekly basis. Sterilization of the dumbbells was conducted by Cobalt-60 irradiation at a dosage of 2.5 Mrad. Several monomer and polymer synthesis examples will be described in the following few pages. l


3

1

Example 1.

1

Synthesis of l,4-bis(p-carboxyphenoxy)butane with N-methylpyrrolidinone (NMP) recrystallization

To a nitrogen purged 5L 3-neck round bottom flask equipped with a reflux condenser, two addition funnels, and a mechanical overhead stirrer, 127.2 grams (3.2 moles) of sodium hydroxide (reagent grade, Fisher) and 600 ml of distilled


68

HOOC


NaOH (aq.) 110°C, 24 hrs.

Figure 1. Synthesis ofl,n-bis(p-carboxyphenoxy)alkane

water were added. The vigorously stirred solution was cooled with an ice-water bath and 219.4 grams (1.6 moles) of p-hydroxybenzoic acid (99%, Aldrich) was slowly added (Figure 1). The temperature of the homogeneous solution was then slowly raised to reflux (110°C) via a heating mantle, and 173.4 grams (0.80 moles) of 1,4dibromobutane (99%, Aldrich) was slowly added, dropwise, through an addition funnel over the course of 6 hours. Over the same timeframe,900 ml of distilled water was slowly added through a second addition funnel to help control the reflux temperature. The temperature of the white slurry was then lowered below the refluxing temperature (80-90°C), and the reaction was allowed to continue for an additional 16 hours. The suspended dicarboxylic sodium salt was then cooled to 60°C and a solution of 33 grams of sodium hydroxide in 100 ml of distilled water was slowly added through the addition funnel. The suspension was then brought to reflux (110°C) for 15 to 30 minutes, cooled to room temperature (25°C), and partially converted to the free dicaroxylic acid by adding one-third portions of the suspended salt to three stirring solutions of 500 ml of hydrochloric acid and 500 ml of distilled water. The stirred suspensions of



69 partially free acid were then heated to 70 C for 2 hours, and suction filtered through a coarse glass frit and allowed to air-dry overnight. Typically, the partially acidified (10 to 15% salt remaining after one acidification as determined by an ash test) monomer was washed one to two more times with 1500 ml of hydrochloric acid and 1500 ml of distilled water, as described above, until an ash free product was formed. The ash free product was allowed to air-dry overnight, and then was washed twice with 750 ml of acetone (99.6%, Fisher) to remove excess water and hydrochloric acid. It was then suction filtered through a Buchner funnel with a coarse glass frit and allowed to air-dry overnight. The air-dried monomer was then dried at room temperature under vacuum to a constant weight (3 to 4 days). The final yield was 220 grams (70%). The white, crude 1,4-bis(p-carboxyphenoxy)butane was then placed in a 4L Erlenmeyer flask and 1750 ml of N-methylpyrrolidinone (99+%, Aldrich) was added to yield an 8 to 1 ratio of solvent to monomer. The stirred solution was then heated to 110°C. After 1 to 2 hours, the acid monomer dissolved. The clear, brown solution was then suctionfilteredto remove particulates, and allowed to stand overnight in afreezer(0°C). The white crystals that formed were isolated by suction filtration and allowed to air dry for 1 to 2 hours. The partially dried monomer was then placed in a 4L Erlenmeyer flask and 1500 ml of NMP was added to yield a 7 to 1 ratio. The stirred solution was then heated to 110°C. After 1 to 2 hours the monomer dissolved, and the light brown solution was suction filtered to remove particulates. The clear solution was placed in a freezer at 0°C and allowed to stand overnight. The white crystals that formed were again isolated by suction filtration, and allowed to air dry for 1 to 2 hours. The partially dried monomer was recrystallized for a third time as described above, yielding a clear, light yellow solution that was allowed to stand overnight at 0°C. The highly pure, white crystals were then isolated for a third time as described above and allowed to air dry for 2 to 3 hours. The crystals were then transferred to a 4L beaker and 1000 ml of distilled water was added (5 to 1 ratio of water to monomer). The stirred white slurry was then heated to 90°C for 2 hours, suction filtered and washed with an additional 1000 ml of hot (90°C) distilled water. The monomer was allowed to air dry for 1 to 2 hours, and then was placed in a 4L beaker along with 1000 ml (5 to 1 ratio) of acetone (99.6%, Fisher), stirred for 1 to 2 hours, suction filtered, washed with an additional 1000 ml of acetone and dried under vacuum at 50°C for 24 hours. The final yield of polymer grade l,4-bis(p-carboxyphenoxy)butane (99.9% pure) was 50 to 60 percent. The preparation, isolation and purification of 1,6-bis(p-carboxyphenoxy)hexane was done in a similar fashion to that described above.


70


Example 2. Synthesis of 1,4-bis(acetoxycarboxyphenoxy)butane To a 5L 1-neck round bottom flask equipped with a magnetic stir bar, distillation head/trap and water condenser, 220 grams of purified l,4-bis(pcarboxyphenoxy)butane and 2750 ml of acetic anhydride (99+%, Aldrich) were added to give a 12.5 to 1 ratio (ml acetic anhydride to monomer). The stirred white suspension was heated to reflux (135°C), giving a clear red-brown solution. The clear solution was concentrated to 875 ml (4 to 1 ratio) by removing acetic acid and acetic anhydride via the distillation head. The solution was slowly cooled to room temperature and then allowed to stand at 0°C overnight (Figure 2). The off-white product, l,4-bis(acetoxycarboxyphenoxy)butane, was isolated by suction filtration under a blanket of nitrogen and allowed to stand for 1 to 2 hours. The anhydride monomer was then transferred to a 2 L beaker and 900 ml of dry ethyl ether (reagent grade, Fisher) was added. The white slurry was stirred for 2 hours under a blanket of nitrogen, suction filtered and dried under vacuum at 50°C for 24 hours. The final yield was 70 to 75 percent. l,6-bis(acetoxycarboxyphenoxy)hexane was synthesized and isolated as described above.

Example 3. Polymerization of l,4-bis(acetoxycarboxyphenoxy)butane To a flamed-out, dry 250 ml 1-neck round bottom flask equipped with an overhead mechanical stirrer, vacuum adapter, 75° adapter, distillate bend with a vacuum take-off and a 50 ml collection flask, 40 grams of freshly prepared 1,4bis(acetoxycarboxyphenoxy)butane was added via a nitrogen purged glove box. The assembly was then secured to a high vacuum (20mins.

Figure 2. Synthesis ofpoly[l,n-bis(p-carboxyphenoxy)alkane anhydride]

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Figure 3. H NMR ofpoly[l,6-bis(p-carboxyphenoxy)hexane anhydride]



73

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Figure 4. HNMR ofpoly[l,6-bis(p-carboxyphenoxy)hexane anhydride] processed at 220°C

brown solution. The clear solution was concentrated to 700 ml (4 to 1 ratio) by removing acetic acid and acetic anhydride via the distillation trap. The solution was slowly cooled to room temperature and then allowed to stand at 0°C overnight (Figure 2). The off-white product, l,6-bis(acetoxycarboxyphenoxy)hexane, was isolated by suction filtration under a blanket of nitrogen and allowed to stand for 1 to 2 hours. The anhydride monomer was then transferred to a 2 L beaker and 300 ml of dry ethyl ether (reagent grade, Fisher) was added. The white slurry was stirred for 2 hours under a blanket of nitrogen, suction filtered and dried under vacuum at 50°C for 24 hours. The final yield was 70 to 75 percent. Twenty-five grams of the mixed anhydride was then added to a 250 ml Erlenmeyer flask along with 125 ml of acetic anhydride and heated, with stirring, to 75°C. After 15 to 30 minutes, the anhydride monomer dissolved. The mixed anhydride was allowed to slowly cool to room temperature and then was cooled to 0°C overnight. The purified anhydride was washed with ethyl ether as described above, and dried overnight under vacuum at 50°C. The final yield was 50 to 60 percent.

Example 6. Polymerization of l,6-bis(acetoxycarboxyphenoxy)hexane from recrystallized anhydride monomer To a flamed-out, dry 250 ml 1-neck round bottom flask equipped with an overhead mechanical stirrer, vacuum adapter, 75° adapter, distillate bend with a vacuum take-off and a 50 ml collection flask, 12 grams of recrystallized



74 (Example 5) l,6-bis(acetoxycarboxyphenoxy)hexane was added via a nitrogen purged glove box. The assembly was then secured to a high vacuum (

High-Strength, Melt Processable, Aromatic Poly(anhydride) - American

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