Method for the manufacture of polymer products from cyclic esters

A method for the manufacture of polymer products from cyclic esters, according to which a catalyst and cyclic monomers are mixed in a mixing chamber and are optionally brought to a higher temperature, after which the mixture is injected, under pressure, into a cavity of a mold consisting of at least two parts and the mold is heated for some time at a temperature above the melting temperature of the monomers, after which the mold is opened and the product is removed from the mold. Polymer products manufactured by this method can be used in medical fields and particularly in reconstructive orthopedics.

The invention relates to a method for the manufacture of polymer products 
from cyclic esters, according to which an amount of cyclic monomers is 
mixed with a catalyst and polymerized. 
BACKGROUND OF THE INVENTION 
Such a method is known from EP-B-0.108.635, according to which an amount of 
cyclic monomers and an amount of catalyst are transferred to a glass 
reactor under dry conditions, for example under a dry stream of N.sub.2. 
The reactor is sealed and the monomers and the catalyst are melted and 
mixed. The polymer is removed from the reactor on completion of the 
reaction. 
In view of the fact that a polymerized polymer of cyclic esters is a rigid 
piece of material, it is usually only possible to remove the material from 
the reactor by breaking the glass wall of the reactor. This is a great 
drawback for applications on an industrial scale, characterized by the 
production of many pieces of material. 
With a method according to EP-B-0.108.635 the material obtained has to be 
processed by milling or melting in order to obtain an object with a usable 
shape. Milling presents the drawback that a large amount of waste is 
obtained, which is economically and ecologically disadvantageous. Melting 
presents the drawback that the microscopic, molecular, structure of the 
material obtained immediately after polymerization, the so-called "as 
polymerized" material, is lost. Several publications state that the "as 
polymerized" structure presents advantages; see for example Makromol. 
Chemie, 188, pp. 1809-1814, 1987. 
Moreover, a number of bonds in the polymer will be broken in melting and as 
a result the molecular weight of the polymer will decrease. 
With a reactor without a separate mixing chamber as in the conventional 
method, in order to mix the monomer and catalyst composition the entire 
reactor is shaken or a magnetic stirring bar is used. Neither of these 
methods leads to a desirable degree of mixing of the catalyst and monomer. 
On the other hand, by mixing the catalyst and monomer in a specially 
designed mixing chamber, a much better mixing occurs. Furthermore, when a 
stirring bar is used, there is the undesirable result of having the 
stirring bar incorporated in the product. 
SUMMARY OF THE INVENTION 
The invention relates to a method for manufacturing polymer products from 
cyclic esters which solves the problems discussed above. 
According to the invention, the catalyst and the cyclic monomers are mixed 
in a mixing chamber and are optionally heated, after which the mixture is 
injected, under pressure, into a cavity of a mold consisting of at least 
two parts, which mold is heated at a temperature above the melting 
temperature of the monomers, after which the polymerization is allowed to 
take place at least partially, after which the mold is opened and the 
product is removed from the mold. 
Such a method is usually referred to as Reaction Injection Molding (RIM). 
RIM is for example described in U.S. Pat. No. 4,524,044 hereby 
incorporated by reference. U.S. Pat. No. 4,524,044 describes RIM for 
lactams, not for cyclic esters as the present invention. 
The method according to the invention can be used to manufacture blocks 
consisting of the polymer product. From these blocks objects of a desired 
shape can then be produced via a finishing step. It is also possible to 
produce objects directly in the shape required, without an extensive 
additional finishing step. 
A further advantage of a RIM method for the processing of cyclic esters is 
that it is possible to fill a mold much more effectively than with the 
conventional method. In the conventional method the components that are to 
react melt in the reactor, which means that the distribution is effected 
by means of gravity. In contrast, according to the present invention, the 
overpressure, with which the components are injected into the mold, 
enables good filling of all angles and depressions in the mold. 
A further advantage of a RIM method for the processing of cyclic esters is 
that the monomers and the catalyst are mixed in a mixing chamber. This 
enables a good distribution of the catalyst throughout the monomers and, 
consequently, good polymerization. 
The catalyst and the monomers can be brought into the mixing chamber at 
room temperature or any other temperature. In the mixing chamber, the 
monomers and the catalyst can be heated to a temperature at which the 
mixture obtains a viscosity that is suitable for injection. This is 
generally above the melting point of the monomers. After the mixture is 
injected into the mold, it is further heated, if necessary, to the reactor 
temperature. The mold can be pre-heated or can be heated after injection. 
Preferably the mold is maintained at a constant temperature during a 
complete serie of processes according to the invention. 
DETAILED DESCRIPTION OF THE INVENTION 
The cyclic esters which are polymerized by a catalyst according to the 
invention can be chosen from, for example, lactones such as lactide, 
glycolide, .epsilon.-caprolactone, dioxanone, 1,4-dioxane-2,3-dione, 
beta-propiolactone, tetramethyl glycolide, beta-butyrolactone, 
gammabutyrolactone or pivalolactone, or cyclic carbonates such as 
trimethylene carbonate, 2,2-dimethyl trimethylene carbonate and the like. 
The lactones can consist of the optically pure isomers or of two or more 
optically different isomers. 
In addition, comonomers based on hydroxycarboxylic acids can be 
incorporated to, for example, 50 wt. % but preferably to no more than 
about 10 wt. %. They can be chosen from, for example, the group 
comprising: 
.alpha.-hydroxybutyric acid, 
.alpha.-hydroxyisobutyric acid, 
.alpha.-hydroxyvaleric acid, 
.alpha.-hydroxyisovaleric acid, 
.alpha.-hydroxycaproic acid, 
.alpha.-hydroxyisocaproic acid, 
.alpha.-hydroxy-.alpha.-ethylbutyric acid, 
.alpha.-hydroxy-.beta.-methylvaleric acid, 
.alpha.-hydroxyheptanoic acid, 
.alpha.-hydroxyoctanoic acid, 
.alpha.-hydroxydecanoic acid, 
.alpha.-hydroxymyristic acid and 
.alpha.-hydroxystearic acid or their intermolecular cyclic esters or 
combinations thereof. 
Cyclic esters and their (co)polymers such as for example: poly(L-lactide); 
poly(D,L-lactide); poly(meso-lactide); poly(glycoilide); 
poly(trimethylenecarbonate); poly(epsilon-caprolactone); 
poly(L-lactide-co-D,L-lactide); poly(L-lactide-co-meso-lactide); 
poly(L-lactide-co-glycolide); poly(L-lactide-co-trimethylenecarbonate); 
poly(L-lactide-co-epsilon-caprolactone); 
poly(D,L-lactide-co-meso-lactide); poly(D,L-lactide-co-glycolide); 
poly(D,L-lactide-co-trimethylenecarbonate); 
poly(D,L-lactide-co-epsilon-caprolactone); 
poly(meso-lactide-co-glycolide); poly(meso-lactide-co-trimethylenecarbonat 
e); poly(meso-lactide-co-epsilon-caprolactone); 
poly(glycolide-co-trimethylenecarbonate); and 
poly(glycolide-co-epsilon-caprolactone). 
Cyclic esters are used as raw materials for polyesters when high molecular 
weights are required. With ring-opening polymerization it is possible to 
continue the reaction to obtain polyesters with high molecular weights. 
With a polycondensation reaction it is only possible to obtain polyesters 
with relatively low molecular weights. 
As catalysts in the method according to the invention, use can be made of 
the usual catalysts known to a person skilled in the art. Examples of such 
catalysts are the catalysts mentioned in EP-B-0.108.635, namely tin 
octoate, antimony trifluoride, zinc powder, dibutyl tin oxide and tin 
oxalate. 
Preferably, use is made of a catalyst characterized in that it consists of 
a compound according to Formula I: 
##STR1## 
where M is a metal ion and n is a number between 1 and 4, equal to the 
valence of the metal ion, and groups R.sup.1 and R.sup.2 are, 
independently of one another, an alkyl, aryl or cycloaliphatic group and 
R.sup.3 is an alkyl, aryl or cylcoaliphatic group or a hydrogen atom. It 
is also possible for the alkyl, aryl or cycloaliphatic groups forming part 
of R.sup.1, R.sup.2 or R.sup.3 to be substituted by halogens. 
M is preferably chosen from a group comprising tin, zinc, lead, bismuth, 
cobalt, iron, manganese and copper ions, more preferably from a group of 
tin, zinc and iron ions and most preferably from zinc or iron ions. If n 
is greater than 1, groups R.sup.1 through R.sup.3 can differ from one 
another in the various configurations. With zinc and tin ions, the 
bivalent ions are preferred. 
The catalyst according to Formula I is advantageous in that the groups 
R.sup.1 through R.sup.3 can be chosen so that, at a desired temperature, 
the catalyst according to Formula 1 is soluble in the monomers which are 
to be catalyzed. 
It is also possible to obtain a catalyst according to Formula I in a 
particularly pure form. 
If M consists of zinc or iron, a catalyst according to Formula I presents 
the added advantage that any resulting metabolic residue will have a low 
toxicity. 
Groups R.sup.1 through R.sup.3 can be chosen independently of another from 
alkyl groups with between 1 and 20 carbon atoms, with or without 
unsaturated bonds, aryl groups or cycloaliphatic groups or several of 
groups R.sup.1 through R.sup.3 together constitute cycloaliphatic ring 
structures. R.sup.1 and R.sup.2 are preferably linear or branched 
aliphatic chains with between 2 and 6 carbon atoms. 
Groups R.sup.1 through R.sup.3 are preferably chosen so that the catalyst 
has a melting point below the melting temperature or in any case below the 
polymerization temperature of the cyclic esters whose reaction is to be 
catalyzed. If this is not the case it is possible that, as the catalyst 
melts in the cyclic ester liquid, the monomers will start to polymerize 
around the still undissolved catalyst salt, thus forming a polymer casing, 
which will prevent further dissolution. Particularly at low polymerization 
temperatures, this slows down the polymerization rate considerably. 
A catalyst with a melting point that is lower than the melting or 
polymerization temperature of the monomers to be polymerized is in the 
context of the invention understood to be a catalyst that dissolves in the 
monomers. This is because the advantage is achieved if the catalyst is 
practically molecularly distributed among the monomers to be polymerized. 
If group M consists of Zn.sup.2 + then groups R.sup.1 and R.sup.2 together 
preferably consist of, in total, between 2 and 6 carbon atoms; in the case 
of the polymerization of lactones, group R.sup.1 more preferably consists 
of tertiary butyl and group R.sup.2 of ethyl. R.sup.3 is then preferably 
H. In that case the compound is called 
zinc-bis(2,2-dimethyl-3,5-heptaneodionato -0,0'). The advantage of such a 
compound is that it has a melting point that lies below the polymerization 
temperature of most lactones, including lactide and glycolide. 
If group M consists of Sn.sup.2 +, groups R.sup.1 and R.sup.2 preferably 
consist of methyl and group R.sup.3 of H. The compound is then called 
tin(II)-bis(2,4-pentanedionato-0,0'). This compound also presents the 
advantage that it has a melting point that lies below the polymerization 
temperature of most lactones, including lactide and glycolide. 
A second Sn catalyst with good properties is a compound according to 
Formula I, where groups R.sup.1 and R.sup.2 consist of t-butyl and R.sup.3 
of H. This compound has a melting point of about 84.degree. C. This tin 
compound presents the added advantage that it is more stable during 
storage than the already known tin octoate. 
A compound according to Formula I can be obtained via the usual synthesis 
routes, such as those described by Kopeckey et al., J. Org. Chem. 27 1036 
(1962) and by Finn et al., J. Chem. Soc. (1938), pp. 1254-1263. 
If groups R.sup.1, R.sup.2 and R.sup.3 are correctly chosen then the 
catalyst according to Formula I will have a melting temperature that lies 
below these polymerization temperatures. This is an advantage because 
otherwise the catalyst will in some cases become encapsulated, as 
described above. 
It is possible to use the catalyst according to Formula I in combination 
with other catalysts. This is of particular advantage if these other 
catalysts also meet the requirements formulated above for the 
aforementioned catalyst, in particular the solubility requirement in the 
material to be polymerized and the low toxicity requirement. 
The monomer/catalyst molecular ratio can on the whole be chosen between 
1,000 and 300,000 and is preferably chosen between 5,000 and 30,000 
(mol/mol). 
The temperature during mixing is chosen such that the components are in a 
liquid state or can be dispersed to such fine particles that the reaction 
can take place without problems. Preferably the reactants are molten 
during or before the mixing. 
The reaction temperature is between 80.degree. and 180.degree. C., 
preferably between 105.degree. and 130.degree. C. 
The pressure used to inject the mixture into the mold is preferably 0.1-5 
bar higher than the pressure in the mold, and more preferably 0.15 to 0.5 
bar higher. The pressure is obtained with the aid of an inert gas such as 
argon, helium or nitrogen. Preferably, use is made of nitrogen. It is 
possible to reduce the pressure in the mold to for example 0.001 bar 
either before or after the mixture is injected. In the last case the 
reduced pressure is applied at the top of the mold. 
Preferably, the reaction is allowed to take place under N.sub.2. This gives 
the further advantage that it is not necessary to maintain a vacuum in the 
mould. Generally, moulds used for RIM are not fitted to maintain a closed 
vacuum with the mould construction: an external pump is necessary. Use of 
such a pump has the disadvantage that volatile monomers from the reaction 
mixtures are sucked out of the mould. 
This reaction time distinguishes the RIM of these cyclic esters from 
conventional RIM systems, in which reaction cycles of 1 to 10 min are 
generally applied. 
It is preferable to use the various components in the purest possible form. 
If nitrogen is used in the process then the nitrogen must have a low 
oxygen content. Cyclic monomers should contain very little contamination 
due to ring-opened cyclic monomers. The amount of H.sub.2 O in the 
reaction must also be minimized. 
The required polymerization duration depends on, among other factors, the 
desired molecular weight and the desired residual monomer content. For 
example in the case of polylactide, a low residual monomer content can be 
advantageous when a low decomposition rate of the polymer implant is 
desired. In general, a polymerization duration of from 30 to 200 hours and 
preferably from 70 to 200 hours will lead to good results. 
Preferably, the degree of conversion is greater than 95%, more preferably 
greater than 98%. The resultant intrinsic viscosity is preferably greater 
than 8, more preferably greater than 11. 
It is possible to obtain polymers with viscosity averages of molecular 
weights of up to at least 1.times.10.sup.6. For example, it is possible to 
synthesize poly-L-lactide, poly-D-lactide or poly-D,L-lactide. 
With the catalyst according to Formula I, it is possible to obtain a new 
polyester composition in which the polyester has a molecular weight of 
between 100,000 and 10,000,000 and an intrinsic viscosity of more than 4, 
obtained by polymerization of cyclic esters in the presence of the 
catalyst. The resulting polyester composition contains between 20 and 500 
ppm zinc and also less than 1,000 ppm of other metals derived from a 
catalyst. 
The product obtained after the polymerization is removed from the mold and 
can be touched up if necessary. For example, the sprue can be removed. If 
the cavity in the mold has more or less the shape of the desired end 
product, as is preferable, the amount of touching up required will be much 
less than the usual amount obtained when conventional methods are used. 
Polymers produced with a method according to the invention can be used in 
numerous fields, but are particularly advantageous as bio-resolvable 
material in biomedical applications and particularly in reconstructive 
orthopedics, as described in the literature. The polymers can be produced 
with high molecular weights and have good mechanical properties, which 
enable them to be used as, for example, bone-setting aids such as plates 
and screws. 
It is also possible to melt the polymers after production and to cast them 
in certain shapes. However, this presents the drawback that the specific 
"as polymerized" structure is broken and, consequently, the specific 
advantages resulting from the "as polymerized" structure are lost. This 
applies particularly to the crystallinity of the structure. Due to the 
relatively poor thermal stability of the polymers and to mechanical 
effects, the polymer chain is broken in several places in melt processing 
and the resultant mechanical properties are poorer. 
The invention also presents the possibility of incorporating fibrous 
reinforcement in the polymer material. This can be done by, for example, 
mixing short fibers with one or both of the liquid components and then 
injecting them into the mold along with the components. Such a method is 
usually referred to as reinforced RIM or R-RIM. 
Preferably, the fibrous reinforcement is placed in the mold before the 
monomer liquid is injected. During injection, the monomers are then washed 
around the fibrous reinforcement, thus wetting the reinforcement. Such 
wetting improves the adhesion of the fiber to the matrix and thus causes 
an overall improvement with respect to the final strength of the composite 
thus formed. Such a method is usually referred to as structural RIM or 
S-RIM. 
The fibrous reinforcement can be in the form of, for example, loose fibers, 
fabrics or mats. The fibers can have any length or thickness. The fibrous 
reinforcement can be chosen from all materials available. Preferably, a 
material is chosen that retains its mechanical properties under the 
reaction conditions of the method according to the invention. 
Examples of fiber materials which can be used in the invention are carbon, 
glass, aramide, natural fibers such as flax or jute, polyethylene, 
polyamide and the like. 
If the polyester material is intended for use in medical applications it is 
preferable to choose a fibrous material that is compatible with biological 
systems. 
If the polyester material is biodegradable, it can be advantageous to use a 
fibrous reinforcement that is also biodegradable. This may be a fiber 
composed of lactide, glycolide, caprolactone and the like or mixtures 
thereof. 
The mixing chamber can be a mixing chamber of the type commonly used in RIM 
methods. 
Preferably, the mixing chamber is a heatable chamber in which the materials 
present can be mixed and in which there are devices for building up a 
pressure sufficient to inject the mixture from the mixing chamber into the 
mold. 
The mold used for the method can consist of any material that is commonly 
used or suitable according to the state of the art. Preferably, the mold 
consists at least partly of metal, for example steel or surgical steel. 
The inside of the mold can be treated to effect a better release of the 
polymer material from the mold. This treatment can consist of polishing or 
coating with a release layer. A release layer can consist of Teflon.TM. or 
of some other polymer material, precious metal coating, titanium nitride, 
etc. 
Preferably, the mold parts are fitted with means for heating the mold, such 
as oil pipes or electric heating elements, or there are provisions for 
placing the mold in its entirety in a heated area. 
If a large number of relatively small objects are to be produced in shapes 
that are virtually the final desired shapes, it is preferable in terms of 
process technology, to connect a series of molds to the mixing chamber and 
to place the entire series of molds in an area having the desired 
temperature and, optionally, pressure. 
It is also possible to place a bag, made of a flexible material, in the 
mold before injection and to then inject the mixture into this bag. This 
is for example described in the Patent Abstracts of Japan, Volume 5, no. 
119 (M-81)(791) of 31 July 1981. In this abstract however is not described 
that this is possible with cyclic esters as in the invention. Use of a bag 
according to the invention presents the advantage that if the bag is 
sealed after injection a sealed reaction chamber is obtained. Any 
pathogenic microorganisms cannot penetrate into this sealed reaction 
chamber. Any microorganisms already present in the mixture is destructed 
during polymerization. If the polymer material is removed from the mold 
together with the already sealed bag, the material will remain sterile in 
the bag. This means that the material no longer has to be sterilized 
before use, which is a substantial advantage. A secondary advantage of 
this bag arrangement is that the requirements usually imposed on the walls 
of the mold can be considerably less stringent, which makes production 
easier. Polymer material which is polymerized in a bag will presumably 
have some form of wrinkling on the surface of the material because the bag 
has not entirely followed the surface of the mold or because the bag has 
seams. If necessary, these irregularities can be removed by slight 
machining. Furthermore, if the bag has a smaller volume than the mold and 
stretches when it is filled, it is possible to achieve virtually no 
wrinkles on the surface of the polymer material. 
Another possibility is to shape the bag in situ in the mold by inflating an 
amount of material suitable for forming a bag into the mold. This has the 
advantage of giving a bag which follows the shape of the mold better and 
has no seams.

EXAMPLES 
The invention will be elucidated by means of the following examples without 
being limited thereto. 
The T.sub.m and the .DELTA.H of specimens of approximately 10 mg were 
measured by means of DSC, using a calibrated Perkin Elmer DSC-7 and a 
scanning rate of 10.degree. C. min.sup.- 1. 
The intrinsic viscosity was determined with the aid of an Ubbelohde 
viscometer, type Oa, in chloroform at 25.degree. C. 
The viscosity average of molecular weight was determined using the formula: 
EQU [.eta.]=(5.45.times.10.sup.- 4).times.M.sub.v.sup.0.73 
according to A. Schindler and D. Harper, J. Polym. Sci., 17, 2593-2599 
(1979), where .eta. is the measured intrinsic viscosity and M.sub.v is the 
viscosity average of molecular weight. 
NMR spectra were recorded using 400 MH.sub.2 NMR equipment. The flexural 
modulus (E), the flexural strength (.sigma.) and the elongation at break 
(e.a.b.) were determined by means of the flexural test according to 
ASTM-D-97. 
The tensile modulus or Young's Modulus (E), the tensile strength (.sigma.) 
and the elongation at break (e.a.b.) were determined by means of the 
tensile test according to ISO-527, type 2. 
The IZOD impact strength was determined according to ASTM 256-A. 
EXAMPLE I 
A mold made of Cr-Ni-Mo steel (type 316L), measuring 
140.times.115.times.27.5 mm (inside measurements), heated at 120.degree. 
C. in a Lauda thermostat, was filled with a reacting L-lactide mixture in 
the following manner: the mold was attached to a thermostatted mixing 
vessel with a volume of 0.50 dm.sup.3 via a sealable coupling. A pressure 
of 1 bar nitrogen (O.sub.2 content&lt;5 ppm; with a dew point at -40.degree. 
C. as regards H.sub.2 O content) was applied via several vacuum/nitrogen 
cycles. Then the coupling between the mixing vessel and the mold was 
sealed and the mixing vessel was filled with 399 grams of L-L-dilactide 
(CCA Biochem), with discharge of N.sub.2. After the lactide crystals had 
been melted at 120.degree. C., 79.8 mg of tin octoate was injected with 
the aid of a Hamilton syringe. After 10 minutes' mixing by means of 
stirring, the reacting melt was introduced into the mold at an elevated 
pressure of 1.2 bar. The mold was disconnected and maintained at 
120.degree. C. for 66 hours, after which it was cooled and opened. 
The shape obtained had a milky white appearance. A sample showed that the 
polymer had an intrinsic viscosity (.eta.) (CHCl.sub.3, 25.degree. C.) of 
9.1 g/dl and a residual monomer content of 0.3%. Thermal analysis yielded 
a .DELTA.H.sub.m of 71.1 J/g, a T.sub.m of 186.3.degree. C. and a T.sub.g 
of 59.6.degree. C. The M.sub.v was calculated from the .eta. and was found 
to be about 600,000. The following mechanical properties were determined 
of the shape obtained: 
Flexural test: E=4.9 GPa, .sigma.=118 MPa, e.a.b.=4.4% 
test: E=4.8 GPa, .sigma.=56 MPa, e.a.b. .TM.6.4% 
mpact test: Izod=3.3+0.1 kJ/m.sup.2. 
EXAMPLE II 
In the same manner as in example I a mixture of 386 g of L,L-dilactide and 
34 g of D,L-lactide was catalyzed by 63 mg (0.015 wt. %) of tin octoate 
for 65 hours at 120.degree. C.: .eta.=9.1 g/dl; the residual monomer 
content was 1.5%, the .DELTA.H.sub.m was 28.4 J/g; the T.sub.m was 
153.3.degree. C. and the T.sub.g was 57.0.degree. C. The mechanical 
properties were good.