WO1995006076A1

WO1995006076A1 - Biodegradable polymers and apparatus and methods for making such polymers

Info

Publication number: WO1995006076A1
Application number: PCT/US1994/009309
Authority: WO
Inventors: Gretchen A. Caywood; Gregory B. Kharas
Original assignee: Dynagen, Inc.
Priority date: 1993-08-20
Filing date: 1994-08-19
Publication date: 1995-03-02
Also published as: CA2169853A1; EP0863932A1; JPH09501973A; AU7568494A

Abstract

The present invention features a biodegradable polymer of the Kreb's cycle type having a weight average molecular weight of 8,000 to 60,000 grams/mole. The invention also features methods and apparatus for making the polymer.

Description

BIODEGRADABLE POLYMERS AND APPARATUS

AND METHODS FOR MAKING SUCH POLYMERS

Field of the Invention

The present invention relates to biodegradable polymers and methods and apparatus for making such polymers.

Embodiments of the present invention feature batch and continuous methods employing condensation polymerization. The apparatus and methods feature greatly increased yield of high molecular weight polymers and improved reproducability.

Background of the Invention

Biodegradable, bioresorbable polymers have applications in medicine and surgery. The term "biodegradable" means capable of being decomposed by natural biological processes. The term "bioresorbable" means capable of being decomposed and utilized by natural processes. The applications include bone replacement, cements, sutures, and drug delivery systems

Typically, biodegradable, bioresorbable polymers are derived from compositions which form part of the normal metabolism of the organism into which the material is to be placed. The acids of the Krebs cycle, also known as the tricarboxylic acid cycle, have been used to form

biodegradable, bioresorbable polymers.

However, use of some Krebs cycle-type polymers has been limited due to the lack of reproducibility of the

polymerization process, insufficient yields of high molecular weight polymer and difficulty in limiting undesired cross linking reactions during the initial polymerization process when synthesizing unsaturated polyesters. Summary of the Invention

The present invention features a biogradable polymer and methods and apparatus for making such polymers. One

embodiment of the present invention features a mixture of biodegradable polymers represented by Formula I below:

As used above, X is a C₂-C₃ divalent paraffinic group or divalent olefinic group, and Y is a C₁-C₅ divalent

paraffinic group or divalent olefinic group or a single bond between the carbon atoms to which it is adjacent. R¹,

R ², R³ and R⁴ taken independently are hydrogen, or a

C₁-C₅ alkyl or alkenyl and n is an integer from 20 to

120. The polymers of the mixture have a weight average molecular weight

of 8,000 - 60,000 g/mole. In this context, the term "mixture" refers to a plurality of polymer molecules having a distribution of chain lengths.

Preferably the mixture has a

of 10,000 - 50,000.

Even more preferred, the mixture has a greater than or equal to 20,000. The mixture of polymers has a number average molecular weight (M_n) of 3,000 to 20,000, with a preferred M_n greater than 5,000 g/mole.

Preferably, X is a C₂ divalent olefinic group and Y is a C₁ divalent paraffinic group or a single bond between adjacent carbons. Preferably R ¹, R², R³ and R⁴ are

hydrogen, or not more than one R ¹ , R², R³ , and R⁴ is

a C₁ alkyl and the remai .ni.ng R ¹ , R², R³, and R⁴ are

H. One embodiment of the present method comprises the steps of forming biodegradable polymer represented by Formula I above. The method comprises forming a reaction mixture comprising a first monomer and a second monomer. The first monomer is represented by the Formula II set forth below:

As used above, Y and R ¹-R⁴ are consistent with Y and

R ¹-R⁴ above. The second monomer is represented by the

Formula III below:

wherein X is consistent with X above, and R ⁵ and R⁶ taken independently are hydrogen, or a C₁-C₃ alkyl or alkenyl.

The method further comprises the step of imposing reaction conditions on the reaction mixture to form a first reaction product. The reaction conditions comprise a temperature in the range of 80° to 250°C under an inert gas. The first reaction product comprises an alcohol by-product which is removed and a first polymer. The first polymer is

represented by the formula IV below:

As used above, Y and X are as set forth above with respect to

Formulas I, II and III, and R⁷ through R¹⁰ and R¹¹

through R ¹⁴ are each R ¹ through R⁴. The method further comprises the step of removing the alcohol by-product and imposing second reaction conditions on the first polymer.

Second reaction conditions comprise a temperature in the range of 80° to 250°C and a pressure of 0.1 -760 torr to form a second reaction product. The second reaction product comprises the first monomer (which is now a by-product) and a mixture of second polymers represented by Formula I above.

The mixture of second polymers have a of 8,000 - 60,000.

The mixture contains an excess of the first monomer.

The method further comprises the step of removing the excess first monomer from the reaction mixture using heat and vacuum to form a high molecular weight biodegradable polymer.

As used herein, the term "biodegradable polymer" refers to polymers which are capable of being resorbed or degraded with minimal residue when placed in a body. Typically such polymers are formed with one or more compositions represented by Formula I or Formula II.

A preferred first monomer comprises physiologically acceptable polyhydroxy alcohols. Preferred polyhydroxy alcohols comprise glycol (1, 2-propanediol), 1, 3-propanediol and ethylene glycol. A preferred polyhydroxy alcohol is propylene glycol.

Preferably, the second monomer is selected from the group of Krebs cycle acids consisting essentially of acotinic acid, isocitric acid, α-keto-glutaric acid, succinic acid, malic acid, oxaloacetic .acid, citric acid, fumaric acid and derivatives thereof. Preferred derivatives are the C₁-C₈ alkyl esters of such acids. A preferred first monomer is fumaric acid and derivatives thereof, including without limitation, diethyl fumarate. Preferably the first and second monomers form a reaction mixture having a mole ratio of 2.2:1 Formula II composition to Formula III composition. For preferred monomers

comprising propylene glycol and diethyl fumarate the mole ratio comprises a first monomer in a concentration of 40 to 60 weight percent and a second monomer in a concentration of 40 to 60 weight percent.

As used herein, the term inert gas refers to gases which are substantially unreactive to the reaction mixture. The term specifically excludes carbon monoxide, carbon dioxide and atmospheric air. One preferred inert gas is nitrogen. Preferably the inert gas is applied as a continuous sweep across the reaction mixture during the first stage of the reaction.

Preferably, the alcohol by-product (produced from the release of the alkoxy groups of the second monomer) is distilled from the reaction mixture.

Preferably, second reaction conditions comprise

reheating the polymer to 195° to 250°C under vacuum to promote further polymerization by removing excess monomer. The vacuum facilitates removal of first monomer promoting further polymerization. Preferably, the vacuum is 1 mm of mercury. Preferably, the second reaction conditions are maintained for 30 to 90 minutes .

As used herein the term "vacuum" implies a pressure which is less than normal atmospheric pressure.

A further embodiment of the present method comprises reaction conditions which include the presence of a

catalyst. Preferably, the catalyst is selected from one or more catalysts set forth in Table 1 below:

TABLE 1

1. Lithium, sodium, potassium, calcium, beryllium,

magnesium, zinc, cadmium, strontium, aluminum, lead, chromium, molybdennum, manganese, iron, cobalt, germanium, nickel, copper, silver, mercury, tin, platinum, boron, antimony, bismuth, palladium, and cerium as the metal, oxide, hydride, formate, acetate, alcoholate, or glycolate or halide salt.

2. Zinc and lead perborates and borates.

3. Zinc, manganous, cobalt, magnesium, and cadmium

succinate, butyrate, adipate, etc. or enolate of a diketone.

4. Calcium, zinc, aluminum, and strontium chlorides and bromides.

5. Lanthanum dioxide and titanate.

6. Neodymium chloride.

7. Double salts of antimony, such as potassium antimonyl tarnate, and salts of antimony acids, such as potassium pyroantimonate.

8. Lithium, zinc, or manganese salts of dithiocarbonic

acids.

9. Titanium tetrafluoride or tetrachloride.

10. Alkyl orthotitanates.

11. Titanium tetrachloride-ether complexes.

12. Quaternary ammonium salts containing a titanium

hexalkoxy radical; titanium tetralkoxides; alkali or alkaline earth metal compounds with aluminum,

zirconium, or titanium alkoxides.

13. Magnesium metal plus free iodine.

14. Organic quaternary ammonium, sulfonium, phosphonium, and oxonium hydroxides and salts.

15. Antimony trioxide, p-toluene sulfonic acid, sulfuric acid, hydrochloric- acid, pyrogallol.

16. Acid catalysts and Lewis acid catalysts; carbonates, alkanoates, hydrides, alkoxides of alkali metals.

Preferred metal catalysts comprise compounds of

magnesium, zinc, cadmium, calcium, strontium, barium, lead, manganese, and cobalt, used separately or together with compounds of antimony, germanium, tin or titanium. Even more preferred metal catalysts comprise those of the transition metals, such as zinc and titanium. These metal catalysts promote polymerization to high molecular weight polymers at lower temperatures than acid catalysts and have less tendency towards cross linking.

Preferred acid catalysts are sulfuric acid, sulfonic acids, hydrochloric acids. A preferred acid catalyst

comprises sulfuric acid or paratoluene sulfonic acid.

Preferred catalysts include para-toluene-sulfonic acid, and zinc and titanium salts and alkoxides. Preferred zinc and titanium salts and alkoxides include zinc chloride, zinc acetate and titanium tetrabutoxide. Preferably, the catalyst is present in the reaction mixture prior to heating the mixture.

In order to control cross linking by free radical reactions, a free radical inhibitor is preferably present prior to heating the reaction mixture. Free radical

inhibitors comprise chloranil, benzoquinone and

hydroquinone. A preferred free radical inhibitor is

hydroquinone.

Embodiments of the present method are suitable for continuous processing. One embodiment of the present method features imposing first reaction conditions upon a reaction mixture in a flow-through reactor to form a first reaction product. The reaction mixture comprises a first monomer and second monomer represented by Formulas II and III as set forth previously. The first reaction product is comprised of an alcohol by-product and a first polymer. The first polymer is represented by Formula- IV as set forth previously. The first reaction product and reaction mixture are received in a second reactor and second reaction conditions are imposed to form a second reaction product. The second reaction product comprises the first monomer and a mixture of polymers

represented by Formula I as set forth previously. Preferably, the first reactor is in continuous

communication with the second reactor in the sense that the reaction mixture and reaction product flow through the first reactor with only limited interruption. Preferably, the second reactor is in continuous communication with one or more vessels for receiving the second reaction product.

First reaction conditions comprise a temperature of 50° to 250°C, and most preferably 80° to 250°C. Preferably, second reaction conditions comprise a pressure of 0.1 to 760 torr and a temperature of 150-250°C. Preferably, second reaction conditions comprise a temperature which is at least 5°C higher than the first reaction conditions. Preferably, reaction conditions comprise continuous stirring, mixing or agitation.

Preferably, following the imposition of second reaction conditions, the second reaction product is devolatilized under devolatilization conditions. Devolatilization

conditions comprise a temperature of 180° to 250°C and a pressure of 0.1 to 10 torr.

Preferably, the volatile gases are removed from the reaction mixture under devolatilization conditions in a devolatilization vessel in communication with the second vessel.

Preferably, the second reaction product is preheated in a separate flow-through heating vessel prior to introduction to the devolatilizer vessel. One preferred devolitilization vessel is a falling strand devolatilizer.

Embodiments of the present invention are able to recycle first and second monomers which are not incorporated in the polymer.

A further embodiment of the present invention features an apparatus for making biodegradable polymers represented by Formula I described previously. One embodiment of the apparatus features a first reactor for receiving and

containing a reaction mixture comprising at least one monomer selected from the group of first and second monomers consisting essentially of a first monomer and a second monomer. The first monomer and the second monomer are represented by the Formulas II and III, respectively, as described previously.

The reactor is capable of imposing reaction conditions on the reaction mixture. Reaction conditions comprise a temperature in the range of 80° to 250°C under an inert gas to form a first reaction product comprising an alcohol by-product and a first polymer. The first polymer is

represented by the Formula IV described previously. The first reactor is in communication with removal means for removing the alcohol by-product. Following the removal of the alcohol by-product, second reaction conditions are imposed on the first polymer. Imposition of second reaction conditions on the first polymer forms a second reaction product comprising a first monomer represented by Formula II above and a mixture of second polymer represented by Formula I above.

The second reaction conditions comprise reheating the polymer to 195° to 250°C under vacuum to promote further polymerization by removal of excess first monomer.

Preferably, the vacuum is 1 mm mercury. Preferably the second reaction conditions are maintained from 30 to 90 minutes.

Preferably, the apparatus further comprises a source of inert gas. A preferred inert gas is nitrogen.

Preferably, removal means comprise distillation

apparatus.

One embodiment of the present invention features a second reactor in fluid communication with the first

reactor. As used herein, the term "fluid communication" means connected to by suitable means such as pipes, conduits, tubing, and the like to allow fluids to flow from one vessel to another. The second reactor is capable of imposing second reaction conditions on the reaction mixture to promote further polymerization. Preferably, the first reactor and the second reactor are capable of receiving catalysts and a free radical inhibitor. Preferably, catalysts and the free radical inhibitors are added to the reaction mixture prior to imposition of reaction conditions in the first reactor. One embodiment of the present apparatus features a source of catalyst in

communication with the first reactor. The catalyst is selected from the group of catalysts set forth in Table I. Particularly preferred catalysts include para-toluene

sulfonic acid, zinc salts and alkoxides and titanium salts and alkoxides.

Preferred reaction conditions comprise temperatures of 195° to 250°C. Preferably, the first and second monomers are present in a mole ratio of 2.2:1. For preferred first and second monomers propylene glycol and diethyl fumarate such ratio results in concentrations of 40 to 60 weight percent for each monomer.

A preferred embodiment of the present invention features a flow-through apparatus for making biodegradable polymers represented by Formula I as set forth above. The apparatus comprises a first reactor and a second reactor. The first reactor and second reactor are in fluid communication. The first reactor is capable of receiving a reaction mixture comprising a first monomer and a second monomer represented by Formulas II and III respectively, as set forth above. The first reactor is capable of imposing first reaction

conditions to form a first reaction product . The first reaction product comprises an alcohol by-product and a first polymer represented by Formula IV above. First reaction conditions comprise a pressure of 0.1 to 760 torr and a temperature of 80 to 250°C. The second reactor is capable of receiving the first polymer from the first reactor and imposing second reaction conditions to form a second reaction product. Second reaction conditions comprise a pressure of 0.1 to 760 torr and a temperature of 80 to 250°C. The second reaction product comprises a second polymer represented by Formula I and the first monomer. The pressure is 0.1 to 760 tons, generally vacuum conditions removes the first monomer format during the second reaction. Preferably, the second reactor has a temperature which is at least 5° higher than the first reactor.

Preferably, the apparatus comprises a devolatilizer assembly for removing volatile gases from the second reaction product following the second reactor. One embodiment of the present apparatus features a devolatilization assembly in fluid communication with the second reactor. The

devolatilization assembly is capable of imposing removal conditions. Removal conditions comprise temperatures of 150° to 250°C and a pressure less than or equal to 10 torr. A preferred apparatus further comprises a falling strand devolatilizer in fluid communication with a preheater

vessel. The preheater vessel is in fluid communication with the second reactor for heating the second reaction product and directing the second reaction product to the falling strand devolatilizer.

The first and second monomers which are not incorporated into the final polymer, are recycled. The first polymer may be purified further if desired.

Embodiments of the present invention provide methods and apparatus for producing polymers of a high molecular range with little or no cross linking. The weight

of the polymers comprises about 8,000 to about 60,000 grams/mole. The continuous process, utilizing a first reactor and a second reactor, allows the process to be scaled to commercial needs and is highly reproducible.

Other features and advantages of the present invention will be apparent from the following description which, by way of illustration, shows preferred embodiments of the present invention and the principles thereof and what is now

considered to be the best mode to apply these principles. Brief Description of the Drawings

FIG. 1 is a schematic of an apparatus for making biodegradable polymers for a first stage of processing;

FIG. 2 is a schematic of the apparatus of FIG. 1 modified for a second stage of processing; and,

FIG. 3 is a schematic representation of a flow-through apparatus for the continuous production of biodegradable polymers.

Detailed Description

Embodiments of the present invention will be described in detail as a batch and a continuous process for the

manufacture of Krebs cycle-type polymers. Individuals skilled in the art will readily recognize that the present invention is subject to modifications and alterations, and the discussion should not be construed as a limitation of the invention but merely an exemplification of the features and advantages.

Turning now to FIG. 1, an apparatus, generally

designated by the numeral 11. for making Krebs cycle-type polymers, is comprised of the following major components: a reaction vessel 13, a column 15, a distillation head 17, a receiving assembly 19, and a heating assembly 21.

Reaction vessel 13 has a opening 23 in communication with a source of nitrogen gas (not shown). Reaction vessel 13 receives nitrogen gas through opening 23 which nitrogen gas flows through the column 15 and distillation head 17 and receiving apparatus 19. Receiving apparatus 19 has a

cooperating opening 25 for removing nitrogen gas from the assembly (i.e., outlet for nitrogen gas). The entire

apparatus 11 is operated under a continuous nitrogen sweep.

Reaction vessel 13 has a second opening 27 for receiving a first monomer and a second monomer. The first monomer and second monomer and optional catalyst and radical inhibitor are combined in vessel 13 to form a reaction mixture.

Preferred monomers comprise diethyl fumarate and propylene glycol. The formation of a reaction mixture of uniform consistency is aided by agitation, mixing, and stirring.

Reaction vessel 13 is equipped with a stirring bar 31 representing stirring means. Vessels of an industrial size will normally have other stirring equipment (not shown) such as paddles, turbines and the like.

Reaction vessel 13 is held within the heating assembly 21. Heating assembly 21 comprises a heater 37 and an oil bath 39 for maintaining reaction vessel 13 at a predetermined temperature. Individuals skilled in the art will recognize that heating assembly 21 can be altered to suit the scale of the reaction process.

Reaction vessel 13 is in communication with column 15. Column 15 is equipped with temperature sensing means, such as a thermometer 41 to monitor the temperature of polymerization reactions in the column 15 and reaction vessel 13.

Column 15 is in communication with distillation head 17. Distillation head 17 is equipped with a water jacket 43 for cooling the interior chamber of the distillation head 17. Cooling of the distillation chamber 17 condenses an alcohol by-product of the polymerization reaction.

Distillation head 17 is in communication with receiving assembly 19. Receiving assembly 19 comprises a housing 45 and a receiving vessel 47. Housing 45 defines a inner chamber having a plurality of openings. One of the openings in housing 45 comprises opening 25 for removal of nitrogen. A further opening is in communication with a receiving vessel 47 for collecting the alcohol by-product produced during the reaction process. A further opening 49 is

equipped with a valve 51. Opening 49 allows the contents of receiving assembly 19 to be removed from the apparatus 11.

During the first reaction stage, apparatus 11 has a configuration as illustrated in FIG. 1. During the first stage a first monomer, such as propylene glycol, and a second monomer, such as diethyl fumarate, are added to the reaction chamber with a catalyst such as zinc chloride and a free radical inhibitor such as hydroquinone, to form a reaction mixture. The propylene glycol and diethyl fumarate are combined (in a 2.2:1 mole ratio). Under a continuous nitrogen sweep, the reaction vessel 13 is heated by the heating assembly 27 to a temperature of approximately 230 °C, over 3 hours. As the oil bath temperature reaches 195°C the temperature at the head of the column 15, as measured by thermometer 41, begins to climb with a steady, rapid

distillation of the alcohol by-product.

As the alcohol evolution becomes rapid, the head temperature will reach well over 78°C, sometimes as high as 160 °C, due to superheating by vapors of the higher boiling monomers being carried up the column by the rapidly

distilling ethanol. As the oil bath temperature reaches 230°C, the distillation of by-products will slow as the theoretical amount of ethanol is recovered into the receiving vessel 47. On the completion of the reaction of the first stage, typically after maintaining the temperature at 230 C for one hour, heating is discontinued and the reaction vessel 13 allowed to cool to below 100°C under a continuous nitorgen sweep .

The first state reaction combines the first and second monomers to form a first reaction product. The first

reaction product comprises the alcohol by-product and a first polymer represented by Formula IV as previously described.

The reaction assembly 11 is now modified for the second stage reaction as generally depicted in FIG. 2. Reference numerals assigned in stage 1 and described with respect to FIG. 1 are maintained in FIG. 2.

The apparatus 11 is modified in FIG. 2. The receiving assembly 15 is replaced with a vacuum pump-dry ice-acetone trap assembly, generally designated by numeral 59. Opening 23 of vessel 13 is closed to allow apparatus 11 to operate under vacuum. Vacuum pump-dry ice-acetone trap assembly 59 is comprised of the following elements, a housing 45a, receiving vessel 47 and a cold trap vessel 61. Housing 45a has an opening 25a. Opening 25a is connected to a

conduit 63. Conduit 63 communicates with a nitrogen source (not shown) through conduit 65 or conduit 63 is closed. The apparatus 11 operates substantially under vacuum and a nitrogen source is not necessary. Nitrogen trapped in the apparatus 11 provides a suitable atmosphere.

Conduit 63 is also in communication with a cold trap vessel 65. Cold trap vessel 65 is capable of being chilled by dry ice or other refrigerating means. The cold trap vessel 65 is in communication with a vacuum source (not shown) via a conduit 67 to allow the apparatus 11 to operate under vacuum. A vacuum gauge (not shown) is in communication with the vacuum source to monitor the vacuum level.

In operation, during stage 2, the system is attached to a vacuum pump by conduit 61. Reaction vessel 13 and its contents are reheated as rapidly as possible (usually over two hours) to 220°C under a vacuum of approximately 1mm.

mercury. Additional distillate is collected in receiving vessel 47a and cold trap vessel 65 as the vessel 13 is heated. The temperature is maintained between 220°C and 225°C for 45 minutes. The melt within the reaction vessel 13 becomes more yellow and viscous during the latter stages. As high-boiling by-products are removed, the distillation temperature may reach 150° or higher. After 45 minutes, heating is discontinued and the reaction vessel 13 is removed from the heat assembly 21. Cooling is continued under evacuation and the clear yellow-gold glassy polymer is dissolved in methylene chloride and precipitated into a

5-fold excess of ethyl ether.

In the stage II reaction, first polymer formed in stage I undergoes further condensation to form a second reaction product. The second reaction product comprises a polymer represented by formula I and first monomer as previously described. The apparatus and methods of FIGS . 1 and 2 are further described with respect to Example 1, discussed later in the application.

One embodiment of the present invention features a continuous process and flow through apparatus. Turning now to FIG. 3, an apparatus, generally designated by the numeral 111, for the continuous manufacture of Krebs cycle-type polymers is illustrated.

The apparatus 111 has the following major elements: a first reactor 113, a second reactor 115, a preheater 117 and a devolatilizer 119. First reactor 113 has a jacket 121 which may be heated by steam, hot oil or pressurized hot water. The first reactor 113 is capable of imposing first reaction conditions on a reaction mixture. First reaction conditions comprise temperatures from 50°C to 250°C and, preferably, from 80°C to 250°C. First reaction conditions also comprise a pressure from 400 to 760 torr under an inert atmosphere of nitrogen.

The first reactor 113 is in communication with a source of a first monomer 123 via a conduit 125 and pump 125a.

Similarly, the first reactor 113 is in communication with a source of a second monomer 127 via a conduit 131 and pump 131a. The first reactor is also in communication with a source of catalyst and free radical inhibitor 133 via a conduit 137 and pump 137a. The first monomer, second

monomer, catalyst and free radical inhibitor are added to the first reactor 113 to form a reaction mixture. The first monomer is represented by formula II and the second monomer is represented by formula III as previously described. The first and second monomers are combined in a mole ratio of 2.2:1.

The reaction mixture in the first reactor is stirred by suitable stirring and mixing means such as turbines, anchors, paddles and screw conveyors (not shown). Reactions

conditions are imposed on the reaction mixture in first reactor 113 by increasing the temperature to 250°C. The residence time in the first reactor is approximately one to six hours and typically converts about 35% to 75% and more preferably 50% to 60% of the monomers to a first reaction product, comprising a first polymer, and an alcohol

by-product. The first polymer is represented by formula IV are previously described.

First reactor 113 is in communication with a condenser 143 via conduit 145. The condenser 143 receives volatile gases comprising the alcohol by-product from the first reaction vessel. The condenser condenses such gases into liquids. The liquids formed with the condenser 143 are piped to a holding tank (not shown) via conduit 147. To the extent possible unreacted first and second monomers are recovered and recycled.

First reaction vessel 113 is in communication with a second reaction vessel 115 via a pump 151 and a conduit 153. The first polymer, formed within the first reactor 113, is pumped to the second reactor 115. Second reactor 115 is capable of imposing second reaction conditions to form a second reaction product. The second reaction product

comprises a mixture of a second polymer represented by formula I as previously described and first monomer.

Second reactor vessel 115, like the first reactor vessel 113, has a jacket 155 for receiving steam, hot oil or

pressurized hot water to set the second reactor 115 at second reaction condition temperatures. Second reaction condition comprise a temperature in a range from 150°C to 250°C and a pressure of 0.1 to 720 torr. More preferably, the operating temperature is 185°C to 2-35°C. Preferably, the temperature is 5° to 10° higher than the temperature of the first reactor 113. Preferably, the pressure is 0.1 - 10 torr.

First reactor 113 operates under an inert atmosphere of nitrogen. Second reactor 115 substantially operates under a vacuum under a nitrogen atmosphere carried from the first reactor 113. Second reactor 115 is in communication with a second condenser 161 via conduit 163. Condenser 161 receives volatile gases comprising any alcohol by-product carried to the second reactor 115 and first monomer from the second reaction within second reactor 115. Condenser 161 condenses such volatile gases to liquids. The liquids formed are piped to a storage tank (not shown) via a conduit 165. To the extent possible, unreacted first and second monomers are recycled.

Second reactor 115 is in communication with preheater 117 by means of a pump 167 and a conduit 169. Preheater 117 is capable of receiving a mixture of second polymer and first monomer. Preheater 117 is capable of imposing

devolatilization conditions. Preheater 117 has suitable heating means such as electric heating coils, hot oils, hot water or steam. Preferably, preheater 117 is equipped with static mixer or a screw conveying means (not shown) to provide a more uniform product. Devolatilization conditions comprise temperatures up to 250°C. Typically, the preheater will be heated to about 180°C to 210°C. The second polymer has a residence time in the preheater of .5 to 15 minutes. Preferably, the time is kept as short as possible to minimize polymer degradation and/or depolymerization or

cross-linking. The pressure in the preheater ranges from 0.1 to 10.4 torr and most preferably is maintained at 1 to 2.4 torr.

Preheater 117 is in communication with the devolatilizer vessel 119 by conduit 171. Devolatilizer vessel 119 operates at a temperature of approximately 150°C to 250°C.

Preferably, devolatilizer vessel 119 operates at a

temperature of 220°C to 240 °C. The internal pressure in the devolatilizer vessel 119 is maintained at a pressure

typically less than 10.4 torr, and most preferably less than about 5 torr.

Preferably, the devolatilizer vessel 119 is a falling strand devolatilizer. The mixture of second polymer and first monomer is received in the devolatilizer vessel 119 and falls through the inner chamber of devolatilizer vessel 119 as strands from top to bottom. As the mixture descends to the bottom of the devolatilizer vessel 119, any unreacted monomers and by-products of the first and second reactions evaporate from the reaction product and are withdrawn from the devolatilizer vessel 119 via a conduit 173. The

unreacted monomers and by-products exiting conduit 173 are received by a third condenser 181. Condenser 181 cools and condenses the alcohol by-product and first and second

monomer. The condensation product is conveyed via conduit 183 to a storage vessel (not shown) . To the extent possible, unreacted first and second monomers are recycled.

The finished second polymer is removed from the

devolatilizer vessel 119 via a pump 185 and a conduit 187.

Individuals skilled in the art will readily recognize that the present apparatus is capable of modification and alteration. Indeed, more than one devolatilizer vessel 119, preheater 117, or additional reaction vessels 113 and 115 may be used.

The resulting second polymer may be extruded as strands, cooled and chopped into pellets or washed with non-solvents to further purify the polymer. The polymer resulting from the process described with respect to the FIG. 3 has a of about 8,000 to 60,000 grams per mole.

These and other features and advantages of the present invention will be described with respect to the following example.

EXAMPLE 1

The following example features formation of a Krebs cycle-type polymer from diethyl fumarate and propylene glycol by transesterification using zinc chloride or zinc acetate as a catalyst. As illustrated in Fig. 1, a reaction vessel 13, a two-liter round-bottom flask containing a stir bar 31, is fitted with a 25 cm Vigreaux column 15 and a water-cooled distillation head 17.

A typical reaction mixture of 344 g diethyl fumarate and 332 g propylene glycol (representing a 2.2:1 glycol: ester ratio) was added to the flask, along with 0.15 g zinc

chloride and 0.05 g hydroquinone. The system was completely flushed with nitrogen, and a nitrogen sweep continued over the reaction during the entire first (atmospheric pressure) stage, by means of an opening 23 on one flask neck and an exit opening 25 at the end of the receiving assembly 19.

The flask 13 was heated by means of an oil bath 39, the temperature slowly being raised to 230 °C over three hours. When the oil bath temperature reached about 195°C, the temperature at the head of the distillation column 15 began to climb, with the steady rapid distillation of ethanol by-product. When ethanol evolution was quite rapid, the head temperature reached well over 78°C, sometimes climbing as high as 160 °C due to superheating by vapors of the higher boiling monomers being carried up the column by the rapidly distilling ethanol. The rate of heating of the oil bath 39 was monitored to assure controlled distillation of the ethanol. By the time the oil bath temperature reached 230°C, the distillation of by-product was slow, the theoretical amount of ethanol usually having completely distilled into the receiver. Some carryover of small amounts of higher boiling materials (monomer) may have occurred. Once the oil bath temperature reached 230 °C, it was maintained at this temperature for one hour. Heating was then discontinued, and the reaction flask 13 allowed to cool to below 100°C under a continuous nitrogen sweep.

At this point, the opening 23 was plugged with a stopper and the system was attached to a vacuum pump, dry ice/acetone trap assembly 59, as can best be seen in Fig. 2. The

reaction mixture was rapidly reheated to 220°C under a vacuum of approximately 1 mm Hg. Additional distillate was

collected as the flask was heated. The temperature was maintained between 220 and 225°C for 45 minutes. The melt became more yellow and viscous during these latter stages.

As high boiling by-products were removed, the distillation temperature reached 150°C or higher. Stirring was maintained for product uniformity. After 45 minutes, heating was discontinued, and the flask 13 was removed from the oil bath

39.

After cooling under continuous evacuation, the clear yellow-gold glassy polymer was either isolated or processed further by dissolving in 200-300 mL methylene chloride and precipitated into a 5-fold excess of ethyl ether. The resulting suspension and precipitate in ether is stored in a freezer overnight. After rewarming to room temperature, the supernatant was decanted, and the precipitation process was repeated. The final precipitate was vacuum dried at room temperature for several days. A typical batch process yields

165-185 g (60-70% yield) of poly (propylene fumarate) having a of about 20,000 g-/mole.

Thus, while preferred embodiments of the invention have been described, the present invention is capable of variation and modification and therefore, the present invention should not be limited to the precise details set forth, but should include such changes and alterations that fall within the purview of the following claims.

Claims

1 . A mixture of biodegradable polymers represented by the formula below :

wherein X is a C₂-C₃ divalent paraffinic group or

divalent olefinic group, and Y is a C₁-C₅ divalent

paraffinic group or divalent olefinic group or a single bond between adjacent carbons, and R¹, R², R³, R⁴ taken

independently are hydrogen, or a C₁-C₅ alkyl or alkenyl and n is an integer from 20 to 120, said polymers in said mixture having a weight average molecular weight of

10,000-50,000.

2. The mixture of biodegradable polymers of claim 2 wherein said weight average molecular weight is greater than or equal to 20,000.

3. The mixture of biodegradable polymers of claim 1 wherein:

X is a C₂ divalent olefinic group, and

Y is a C₁ divalent paraffinic group, or a single bond between the adjacent carbons, and R ¹ , R², R³ and

R⁴ are hydrogen, or not more than one of R ¹ , R², R³

and R⁴ is a C₁ alkyl and the remaining R ¹ , R², R³

and R⁴ are hydrogen.

4. A method of making a biodegradable polymer

represented by the formula below:

wherein X is a C₂-C₃ divalent paraffinic group or

divalent olefinic group, and Y is a C₁-C₅ divalent

paraffinic group or divalent olefinic group or a single bond between adjacent carbons, and R ¹, R², R³ and R⁴ taken independently are hydrogen, or a C₁-C₅ alkyl or alkenyl and n is an integer from 20 to 60, comprising:

(a) forming a reaction mixture comprising a first monomer and a second monomer wherein said first monomer is represented by the formula:

wherein Y and R ¹ , R², R³ and R⁴ are as

described above and said second monomer is represented by the formula:

wherein X is described above and R ⁵ and R⁶ taken independently are H, or a C₁ - C₃ alkyl or alkenyl;

(b) imposing first reaction conditions on said reaction mixture, said reaction conditions comprising a temperature in the range of 80° - 250°C, and an atmosphere of inert gas, to form a first product comprising an alcohol by-product and a first polymer having a formula:

wherein Y and X are as set forth above, and R⁷ through

R¹⁰ are R¹ through R⁴ and R¹¹ through R¹⁴ are each

R¹ through R⁴;

(c) removing the alcohol by-product from the reaction mixture; (d) subjecting the first product to second reaction conditions comprising a temperature in the range of 80 - 250°C and a pressure of 0.1-760 torr to form a second

reaction product comprising the first monomer and mixture of a second polymers having the formula of said biodegradable polymer, said mixture of second polymers having a weight average molecular weight of 10,000-50,000.

5. The method of claim 4 wherein said second polymer has a weight average molecular weight of greater than or equal to 20,000.

6. The method of claim 4 wherein said first monomer and second monomer of said reaction have a mole ratio of 2.2:1.

7. The method of claim 4 wherein said inert gas is nitrogen.

8. The method of claim 4 wherein said alcohol

by-product is distilled from the reaction mixture.

9. The method of claim 4 wherein said pressure is 0.1 - 10 torr.

10. The method of claim 4 wherein said second reaction conditions comprise a temperature of 185 - 235°C.

11. The method of claim 4 wherein at least one of said first and second reaction conditions include the presence of a catalyst.

12. The method of claim 11 wherein said catalyst is present prior to imposing first reaction conditions.

13. The method of claim 11 wherein said catalyst is selected from the group of catalyst consisting essentially of acid catalysts, Lewis acid catalysts or transition metal catalysts.

14. The method of claim 11 wherein said catalyst is selected from the group of catalysts consisting essentially of para-toluene sulfonic acid, salts and acetates of zinc, and titanium alcoholates.

15. The method of claim 14 wherein said catalyst is selected for the group consisting essentially of zinc

chloride, zinc acetate, and titanium tetrabutoxide.

16. The method of claim 4 wherein at least one of said reaction conditions include the presence of a free radical inhibitor.

17. The method of claim 15 wherein said free radical inhibitor is present prior to imposing first reaction

conditions.

18. The method of claim 4 wherein said reaction

conditions comprise temperatures of 195 - 250°C.

19. The method of claim 4 wherein said first monomer is selected from the group of monomers comprising 1,2

propanediol, 1,3 propanediol, and ethylene glycol.

20. The method of claim 4 wherein said second monomer is diethyl fumarate.

21. The method of claim 4 wherein said first monomer is 1,2 propanediol and said second monomer is diethyl fumarate.

22. The method of claim 21 wherein said first monomer is present in a concentration of 40-60 weight percent and second monomer is present in a concentration of 40-60 weight percent.

23. The method of claim 4 wherein said reaction

conditions are imposed in a first flow through reactor having an operating pressure of 0.1 to 760 torr.

24. The method of claim 4 wherein said second reaction conditions are imposed in a second flow-through reactor.

25. The method of claim 24 wherein said second reactor has a temperature which is at least 5°C higher than said first reactor.

26. The method of claim 4 wherein said volatile gases are removed from the second polymer under removal

conditions, said removal conditions comprising a temperature of 180°C - 250°C and a pressure less than or equal to 10 torr.

27. The method of claim 26 wherein said removal

conditions comprise a temperature of 150 - 250 °C and a

pressure of 0.1 to 10 torr.

28. The method of claim 26 wherein said removal

conditions are imposed within a falling strand devolatilizer.

29. The method of claim 4 wherein said reaction mixture is continuously stirred.

30. The process of claim 4 wherein said first and second monomers which are not incorporated in said polymer are recycled.

31. An apparatus for making biodegradable polymers represented by the formula set forth below:

wherein X is a C₂-C₃ divalent paraffinic group or

divalent olefinic group and Y is a C₁-C₅ divalent

paraffinic group or divalent olefinic group or a single bond between adjacent carbons, and R ¹, R², R³ , R⁴ taken

independently are hydrogen, or a C₁-C₅ alkyl or alkenyl and n is an integer from 20 to 120, comprising:

A first reaction vessel, a second reaction vessel, and a devolatilizer assembly, said first reaction vessel for receiving and containing a reaction mixture comprising a first monomer and a second monomer wherein said first monomer is represented by the formula below:

wherein Y, R¹ , R² , R³ and R ⁴ are as described above

and said second monomer is represented by the formula :

wherein X is as described above and R ⁵ and R⁶ taken

independently are H, or a C₁ - C₃ alkyl or alkenyl; said first reaction vessel capable of imposing first reaction conditions on said reaction mixture, said reaction conditions comprising a temperature in the range of 80° - 250°, and an atmosphere of inert gas, to form a first reaction product comprising an alcohol by-product and a first polymer, said first polymer having a formula as set forth below:

said second reaction vessel capable to receiving said first polymer and imposing second reaction conditions, said second reaction conditions comprising a temperature in the range of 250°C at a pressure of 0.1 - 720 torr to form a mixture of second polymer having the formula of said biodegradable polymer, said second polymer having a weight average

molecular weight of 8,000 - 60,000 g/mole.

32. The apparatus of claim 31 wherein said pressure vacuum is 0.1 - 10 torr.

33. The apparatus of claim 31 wherein said second reaction conditions comprise a temperature of 185 - 235°C.

34. The apparatus of claim 31 wherein at least one of said first and second reaction conditions include the

presence of a catalyst.

35. The apparatus of claim 31 wherein said inert gas is nitrogen.

36. The apparatus of claim 31 wherein said first monomer and second monomer are present in said first reaction mixture in a mole ratio of 2.2:1.